Publications by year
In Press
Altwiley D, Brignoli T, Edwards A, Recker M, Lee J, Massey RC (In Press). A Functional Menadione Biosynthesis Pathway is Required for Capsule Production by <i>Staphylococcus aureus</i>.
Abstract:
A Functional Menadione Biosynthesis Pathway is Required for Capsule Production by Staphylococcus aureus
AbstractStaphylococcus aureus is a major human pathogen that utilises a wide array of pathogenic and immune evasion strategies to cause disease. One immune evasion strategy, common to many bacterial pathogens, is the ability of S. aureus to produce a capsule that protects the bacteria from several aspects of the human immune system. To identify novel regulators of capsule production by S. aureus we applied a genome wide association study (GWAS) to a collection of 300 bacteraemia isolates that represent the two major MRSA clones in UK and Irish hospitals: CC22 and CC30. One of the loci associated with capsule production, the menD gene, encodes an enzyme critical to the biosynthesis of menadione. Mutations in this gene that result in menadione auxotrophy induce the slow growing small-colony variant (SCV) form of S. aureus often associated with chronic infections due to their increased resistance to antibiotics and ability to survive inside phagocytes. Utilising such an SCV we functionally verified this association between menD and capsule production. Although the clinical isolates with polymorphisms in the menD gene in our collections had no apparent growth defects, they were more resistant to gentamicin when compared to those with the wild-type menD gene. Our work suggests that menadione plays a critical role in the production of the S. aureus capsule, and that amongst clinical isolates polymorphisms exist in the menD gene that confer the characteristic increased gentamicin resistance, but not the major growth defect associated with SCV phenotype.
Abstract.
Douglas EJA, Palk N, Brignoli T, Altwiley D, Boura M, Laabei M, Recker M, Cheung GYC, Liu R, Hsieh RC, et al (In Press). Extensive re-modelling of the cell wall during the development of<i>Staphylococcus aureus</i>bacteraemia.
Abstract:
Extensive re-modelling of the cell wall during the development ofStaphylococcus aureusbacteraemia
Introductory Paragraph / AbstractThe bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogenStaphylococcus aureusmanages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes,tcaA, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of this protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations intcaAare selected for during bacteraemia, this protein positively contributes to the virulence ofS. aureusthrough its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.
Abstract.
Klümper U, Recker M, Zhang L, Yin X, Zhang T, Buckling A, Gaze W (In Press). Selection for antibiotic resistance is reduced when embedded in a natural microbial community.
Abstract:
Selection for antibiotic resistance is reduced when embedded in a natural microbial community
AbstractAntibiotic resistance has emerged as one of the most pressing, global threats to public health. In single-species experiments selection for antibiotic resistance occurs at very low antibiotic concentrations. However, it is unclear how far these findings can be extrapolated to natural environments, where species are embedded within complex communities. We competed isogenic strains of Escherichia coli, differing exclusively in a single chromosomal resistance determinant, in the presence and absence of a pig fecal microbial community across a gradient of antibiotic concentration for two relevant antibiotics: gentamicin and kanamycin. We show that the minimal selective concentration was increased by more than one order of magnitude for both antibiotics when embedded in the community. We identified two general mechanisms were responsible for the increase in minimal selective concentration: an increase in the cost of resistance and a protective effect of the community for the susceptible phenotype. These findings have implications for our understanding of the evolution and selection of antibiotic resistance, and can inform future risk assessment efforts on antibiotic concentrations.
Abstract.
Douglas E, Brignoli T, Recker M, O’Brien E, McLoughlin RM, Massey RC (In Press). Self-sensitisation of <i>Staphylococcus aureus</i> to the antimicrobial factors found in human blood.
Abstract:
Self-sensitisation of Staphylococcus aureus to the antimicrobial factors found in human blood
Introductory ParagraphFor opportunistic pathogens, the switch from a commensal to an invasive lifestyle is often considered an accidental event. But with plentiful opportunity, what leads one accidental event to result in an invasive infection, and another not to? and how much of this apparent stochasticity is driven by bacterial factors? to answer these questions, here we focussed on the major human pathogen Staphylococcus aureus, which can both reside asymptomatically as a member of our respiratory microbiome, or become invasive and cause infections as severe as bacteraemia. Survival upon exposure to the antibacterial factors found in serum is a critical aspect of their ability to cause bacteraemia, and across a collection of 300 clinical isolates we found there to be significant variability in this capability. Utilising a GWAS approach we have uncovered the genetic basis of much of this variability through the identification and functional verification of a number of new polymorphic loci that affect serum survival: tcaA, tarK, gntR, ilvC, arsB, yfhO, and pdhD. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, while simultaneously enhancing the sensitivity of S. aureus to serum through a process involving the ligation of wall teichoic acids into the cell wall. As blood-stage infections are a transmission dead-end for the bacteria, that S. aureus actively responds to serum to produce a protein which specifically limits their ability to survive in this environment demonstrates that the switch from the commensal to the invasive lifestyle is complex, and that TcaA may contribute to the long-term success of S. aureus by restricting the bacteria to their more readily transmissible commensal state.
Abstract.
2023
Olmo RP, Todjro YMH, Aguiar ERGR, de Almeida JPP, Ferreira FV, Armache JN, de Faria IJS, Ferreira AGA, Amadou SCG, Silva ATS, et al (2023). Mosquito vector competence for dengue is modulated by insect-specific viruses.
Nat Microbiol,
8(1), 135-149.
Abstract:
Mosquito vector competence for dengue is modulated by insect-specific viruses.
Aedes aegypti and A. albopictus mosquitoes are the main vectors for dengue virus (DENV) and other arboviruses, including Zika virus (ZIKV). Understanding the factors that affect transmission of arboviruses from mosquitoes to humans is a priority because it could inform public health and targeted interventions. Reasoning that interactions among viruses in the vector insect might affect transmission, we analysed the viromes of 815 urban Aedes mosquitoes collected from 12 countries worldwide. Two mosquito-specific viruses, Phasi Charoen-like virus (PCLV) and Humaita Tubiacanga virus (HTV), were the most abundant in A. aegypti worldwide. Spatiotemporal analyses of virus circulation in an endemic urban area revealed a 200% increase in chances of having DENV in wild A. aegypti mosquitoes when both HTV and PCLV were present. Using a mouse model in the laboratory, we showed that the presence of HTV and PCLV increased the ability of mosquitoes to transmit DENV and ZIKV to a vertebrate host. By transcriptomic analysis, we found that in DENV-infected mosquitoes, HTV and PCLV block the downregulation of histone H4, which we identify as an important proviral host factor in vivo.
Abstract.
Author URL.
2022
Addy JWG, Bediako Y, Ndungu FM, Valetta JJ, Reid AJ, Mwacharo J, Ngoi JM, Wambua J, Otieno E, Musyoki J, et al (2022). 10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity.
Wellcome Open Research,
6, 79-79.
Abstract:
10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity
Background: Studies of long-term malaria cohorts have provided essential insights into how Plasmodium falciparum interacts with humans, and influences the development of antimalarial immunity. Immunity to malaria is acquired gradually after multiple infections, some of which present with clinical symptoms. However, there is considerable variation in the number of clinical episodes experienced by children of the same age within the same cohort. Understanding this variation in clinical symptoms and how it relates to the development of naturally acquired immunity is crucial in identifying how and when some children stop experiencing further malaria episodes. Where variability in clinical episodes may result from different rates of acquisition of immunity, or from variable exposure to the parasite. Methods: Using data from a longitudinal cohort of children residing in an area of moderate P. falciparum transmission in Kilifi district, Kenya, we fitted cumulative episode curves as monotonic-increasing splines, to 56 children under surveillance for malaria from the age of 5 to 15. Results: There was large variability in the accumulation of numbers of clinical malaria episodes experienced by the children, despite being of similar age and living in the same general location. One group of children from a particular sub-region of the cohort stopped accumulating clinical malaria episodes earlier than other children in the study. Despite lack of further clinical episodes of malaria, these children had higher asymptomatic parasite densities and higher antibody titres to a panel of P. falciparum blood-stage antigens. Conclusions: This suggests development of clinical immunity rather than lack of exposure to the parasite, and supports the view that this immunity to malaria disease is maintained by a greater exposure to P. falciparum, and thus higher parasite burdens. Our study illustrates the complexity of anti-malaria immunity and underscores the need for analyses which can sufficiently reflect the heterogeneity within endemic populations.
Abstract.
Brignoli T, Recker M, Lee WWY, Dong T, Bhamber R, Albur M, Williams P, Dowsey AW, Massey RC (2022). Diagnostic MALDI-TOF MS can differentiate between high and low toxic Staphylococcus aureus bacteraemia isolates as a predictor of patient outcome.
Microbiology (Reading),
168(8).
Abstract:
Diagnostic MALDI-TOF MS can differentiate between high and low toxic Staphylococcus aureus bacteraemia isolates as a predictor of patient outcome.
Staphylococcus aureus bacteraemia (SAB) is a major cause of blood-stream infection (BSI) in both healthcare and community settings. While the underlying comorbidities of a patient significantly contributes to their susceptibility to and outcome following SAB, recent studies show the importance of the level of cytolytic toxin production by the infecting bacterium. In this study we demonstrate that this cytotoxicity can be determined directly from the diagnostic MALDI-TOF mass spectrum generated in a routine diagnostic laboratory. With further development this information could be used to guide the management and improve the outcomes for SAB patients.
Abstract.
Author URL.
Andrade CM, Fleckenstein H, Thomson-Luque R, Doumbo S, Lima NF, Anderson C, Hibbert J, Hopp CS, Tran TM, Li S, et al (2022). Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season (vol 26, pg 1929, 2020).
NATURE MEDICINE,
28(10), 2216-2216.
Author URL.
Valletta JJ, Addy JWG, Reid AJ, Ndungu FM, Bediako Y, Mwacharo J, Mohammed KS, Musyoki J, Ngoi JM, Wambua J, et al (2022). Individual-level variations in malaria susceptibility and acquisition of clinical protection.
Wellcome Open Research,
6, 22-22.
Abstract:
Individual-level variations in malaria susceptibility and acquisition of clinical protection
After decades of research, our understanding of when and why individuals infected with Plasmodium falciparum develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these inter-individual variations, we analysed the long-term malaria epidemiology of children ≤12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort’s limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria episodes. Besides exposure to the parasite, measured as disease prevalence in the surrounding area, we find that the birth time of year has an independent effect on the individual’s risk of experiencing a clinical episode. Furthermore, our analyses reveal that those children with a history of an above average number of episodes are more likely to experience further episodes during the upcoming transmission season. These findings are indicative of phenotypic differences in the rates by which children acquire clinical protection to malaria and offer important insights into the natural variability underlying malaria epidemiology.
Abstract.
Stevens EJ, Morse DJ, Bonini D, Duggan S, Brignoli T, Recker M, Lees JA, Croucher NJ, Bentley S, Wilson DJ, et al (2022). Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae.
Microb Genom,
8(4).
Abstract:
Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae.
Streptococcus pneumoniae is a major human pathogen that can cause severe invasive diseases such as pneumonia, septicaemia and meningitis. Young children are at a particularly high risk, with an estimated 3-4 million cases of severe disease and between 300 000 and 500 000 deaths attributable to pneumococcal disease each year. The haemolytic toxin pneumolysin (Ply) is a primary virulence factor for this bacterium, yet despite its key role in pathogenesis, immune evasion and transmission, the regulation of Ply production is not well defined. Using a genome-wide association approach, we identified a large number of potential affectors of Ply activity, including a gene acquired horizontally on the antibiotic resistance-conferring Integrative and Conjugative Element (ICE) ICESp23FST81. This gene encodes a novel modular protein, ZomB, which has an N-terminal UvrD-like helicase domain followed by two Cas4-like domains with potent ATP-dependent nuclease activity. We found the regulatory effect of ZomB to be specific for the ply operon, potentially mediated by its high affinity for the BOX repeats encoded therein. Using a murine model of pneumococcal colonization, we further demonstrate that a ZomB mutant strain colonizes both the upper respiratory tract and lungs at higher levels when compared to the wild-type strain. While the antibiotic resistance-conferring aspects of ICESp23FST81 are often credited with contributing to the success of the S. pneumoniae lineages that acquire it, its ability to control the expression of a major virulence factor implicated in bacterial transmission is also likely to have played an important role.
Abstract.
Author URL.
2021
Addy JWG, Bediako Y, Ndungu FM, Valetta JJ, Reid AJ, Mwacharo J, Ngoi JM, Wambua J, Otieno E, Musyoki J, et al (2021). 10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity.
Wellcome Open Research,
6, 79-79.
Abstract:
10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity
Background: Studies of long-term malaria cohorts have provided essential insights into how Plasmodium falciparum interacts with humans, and influences the development of antimalarial immunity. Immunity to malaria is acquired gradually after multiple infections, some of which present with clinical symptoms. However, there is considerable variation in the number of clinical episodes experienced by children of the same age within the same cohort. Understanding this variation in clinical symptoms and how it relates to the development of naturally acquired immunity is crucial in identifying how and when some children stop experiencing further malaria episodes. Where variability in clinical episodes may result from different rates of acquisition of immunity, or from variable exposure to the parasite. Methods: Using data from a longitudinal cohort of children residing in an area of moderate P. falciparum transmission in Kilifi district, Kenya, we fitted cumulative episode curves as monotonic-increasing splines, to 56 children under surveillance for malaria from the age of 5 to 15. Results: There was large variability in the accumulation of numbers of clinical malaria episodes experienced by the children, despite being of similar age and living in the same general location. One group of children from a particular sub-region of the cohort stopped accumulating clinical malaria episodes earlier than other children in the study. Despite lack of further clinical episodes of malaria, these children had higher asymptomatic parasite densities and higher antibody titres to a panel of P. falciparum blood-stage antigens. Conclusions: This suggests development of clinical immunity rather than lack of exposure to the parasite, and supports the view that this immunity to malaria disease is maintained by a greater exposure to P. falciparum, and thus higher parasite burdens. Our study illustrates the complexity of anti-malaria immunity and underscores the need for analyses which can sufficiently reflect the heterogeneity within endemic populations.
Abstract.
Addy JWG, Bediako Y, Ndungu FM, Valetta JJ, Reid AJ, Mwacharo J, Ngoi JM, Wambua J, Otieno E, Musyoki J, et al (2021). 10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity. Wellcome Open Research, 6
Altwiley D, Brignoli T, Edwards A, Recker M, Lee JC, Massey RC (2021). A functional menadione biosynthesis pathway is required for capsule production by Staphylococcus aureus.
Microbiology (United Kingdom),
167(11).
Abstract:
A functional menadione biosynthesis pathway is required for capsule production by Staphylococcus aureus
Staphylococcus aureus is a major human pathogen that utilises a wide array of pathogenic and immune evasion strategies to cause disease. One immune evasion strategy, common to many bacterial pathogens, is the ability of S. aureus to produce a capsule that protects the bacteria from several aspects of the human immune system. To identify novel regulators of capsule production by S. aureus, we applied a genome wide association study (GWAS) to a collection of 300 bacteraemia isolates that represent the two major MRSA clones in UK and Irish hospitals: CC22 and CC30. One of the loci associated with capsule produc-tion, the menD gene, encodes an enzyme critical to the biosynthesis of menadione. Mutations in this gene that result in mena-dione auxotrophy induce the slow growing small-colony variant (SCV) form of S. aureus often associated with chronic infections due to their increased resistance to antibiotics and ability to survive inside phagocytes. Utilising such an SCV, we functionally verified this association between menD and capsule production. Although the clinical isolates with polymorphisms in the menD gene in our collections had no apparent growth defects, they were more resistant to gentamicin when compared to those with the wild-type menD gene. Our work suggests that menadione is involved in the production of the S. aureus capsule, and that amongst clinical isolates polymorphisms exist in the menD gene that confer the characteristic increased gentamicin resistance, but not the major growth defect associated with SCV phenotype.
Abstract.
Attrill EL, Claydon R, Łapińska U, Recker M, Meaden S, Brown AT, Westra ER, Harding SV, Pagliara S (2021). Individual bacteria in structured environments rely on phenotypic resistance to phage.
PLoS Biol,
19(10).
Abstract:
Individual bacteria in structured environments rely on phenotypic resistance to phage.
Bacteriophages represent an avenue to overcome the current antibiotic resistance crisis, but evolution of genetic resistance to phages remains a concern. In vitro, bacteria evolve genetic resistance, preventing phage adsorption or degrading phage DNA. In natural environments, evolved resistance is lower possibly because the spatial heterogeneity within biofilms, microcolonies, or wall populations favours phenotypic survival to lytic phages. However, it is also possible that the persistence of genetically sensitive bacteria is due to less efficient phage amplification in natural environments, the existence of refuges where bacteria can hide, and a reduced spread of resistant genotypes. Here, we monitor the interactions between individual planktonic bacteria in isolation in ephemeral refuges and bacteriophage by tracking the survival of individual cells. We find that in these transient spatial refuges, phenotypic resistance due to reduced expression of the phage receptor is a key determinant of bacterial survival. This survival strategy is in contrast with the emergence of genetic resistance in the absence of ephemeral refuges in well-mixed environments. Predictions generated via a mathematical modelling framework to track bacterial response to phages reveal that the presence of spatial refuges leads to fundamentally different population dynamics that should be considered in order to predict and manipulate the evolutionary and ecological dynamics of bacteria-phage interactions in naturally structured environments.
Abstract.
Author URL.
Valletta JJ, Addy JWG, Reid AJ, Ndungu FM, Bediako Y, Mwacharo J, Said K, Musyoki J, Ngoi JM, Wambua J, et al (2021). Individual-level variations in malaria susceptibility and acquisition of clinical protection.
Wellcome Open Research,
6, 22-22.
Abstract:
Individual-level variations in malaria susceptibility and acquisition of clinical protection
After decades of research, our understanding of when and why individuals infected with Plasmodium falciparum develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these inter-individual variations, we analysed the long-term malaria epidemiology of children ≤12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort’s limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria episodes. Besides exposure to the parasite, measured as disease prevalence in the surrounding area, we find that the birth time of year has an independent effect on the individual’s risk of experiencing a clinical episode. Furthermore, our analyses reveal that those children with a history of an above average number of episodes are more likely to experience further episodes during the upcoming transmission season. These findings are indicative of phenotypic differences in the rates by which children acquire clinical protection to malaria and offer important insights into the natural variability underlying malaria epidemiology.
Abstract.
Valletta JJ, Addy JWG, Reid AJ, Ndungu FM, Bediako Y, Mwacharo J, Said K, Musyoki J, Ngoi JM, Wambua J, et al (2021). Individual-level variations in malaria susceptibility and acquisition of clinical protection.
Wellcome Open Research,
6, 22-22.
Abstract:
Individual-level variations in malaria susceptibility and acquisition of clinical protection
After decades of research, our understanding of when and why individuals infected with Plasmodium falciparum develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these inter-individual variations, we analysed the long-term malaria epidemiology of children ≤12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort’s limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria episodes. Besides exposure to the parasite, measured as disease prevalence in the surrounding area, we find that the birth time of year has an independent effect on the individual’s risk of experiencing a clinical episode. Furthermore, our analyses reveal that those children with a history of an above average number of episodes are more likely to experience further episodes during the upcoming transmission season. These findings are indicative of phenotypic differences in the rates by which children acquire clinical protection to malaria and offer important insights into the natural variability underlying malaria epidemiology.
Abstract.
2020
Silva-Filho JL, Lacerda MVG, Recker M, Wassmer SC, Marti M, Costa FTM (2020). Erratum: Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous: (Trends in Parasitology 36, 447–458, 2020) (Trends in Parasitology (2020) 36(5) (447–458), (S1471492220300611), (10.1016/j.pt.2020.03.002)).
Trends in Parasitology,
36(7), 648-649.
Abstract:
Erratum: Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous: (Trends in Parasitology 36, 447–458, 2020) (Trends in Parasitology (2020) 36(5) (447–458), (S1471492220300611), (10.1016/j.pt.2020.03.002))
[Figure presented] the previous Figure 3 indicated that reticulocyte- and APC- expressed MHC I interacts with PRRs in the BM cells (HSCs, MPPs, and ECs), which is wrong. MHC I can only interact with TCR-CD8 T cells. This error has been corrected in the figure shown here and in the online article.
Abstract.
Andrade CM, Fleckenstein H, Thomson-Luque R, Doumbo S, Lima NF, Anderson C, Hibbert J, Hopp CS, Tran TM, Li S, et al (2020). Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season. Nature Medicine, 26(12), 1929-1940.
Silva-Filho JL, Lacerda MVG, Recker M, Wassmer SC, Marti M, Costa FTM (2020). Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous.
Trends in Parasitology,
36(5), 447-458.
Abstract:
Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous
Estimation of Plasmodium vivax biomass based on circulating biomarkers indicates the existence of a predominant biomass outside of the circulation that is not captured by peripheral parasitemia, in particular in patients with complicated outcomes. A series of recent studies have suggested that the hematopoietic niche of the bone marrow (BM) is a major reservoir for parasite replication and the development of transmission stages. However, significant knowledge gaps remain in our understanding of host–parasite interactions, pathophysiology, and the implications for treatment and diagnosis of such a reservoir. Here, we discuss the current status of this emerging research field in the context of P. vivax.
Abstract.
Stevens EJ, Morse DJ, Bonini D, Duggan S, Brignoli T, Recker M, Lees JA, Croucher NJ, Bentley S, Wilson DJ, et al (2020). Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae.
Tennant W (2020). The Effects of Spatio-Temporal Heterogeneities on the Emergence and Spread of Dengue Virus.
Abstract:
The Effects of Spatio-Temporal Heterogeneities on the Emergence and Spread of Dengue Virus
The dengue virus (DENV) remains a considerable global public health concern. The interactions between the virus, its mosquito vectors and the human host are complex and only partially understood. Dependencies of vector ecology on environmental attributes, such as temperature and rainfall, together with host population density, introduce strong spatiotemporal heterogeneities, resulting in irregular epidemic outbreaks and asynchronous oscillations in serotype prevalence. Human movements across different spatial scales have also been implicated as important drivers of dengue epidemiology across space and time, and further create the conditions for the geographic expansion of dengue into new habitats. Previously proposed transmission models often relied on strong, unrealistic assumptions regarding key epidemiological and ecological interactions to elucidate the effects of these spatio-temporal heterogeneities on the emergence, spread and persistence of dengue. Furthermore, the computational limitations of individual based models have hindered the development of more detailed descriptions of the influence of vector ecology, environment and human mobility on dengue epidemiology.
In order to address these shortcomings, the main aim of this thesis was to rigorously quantify the effects of ecological drivers on dengue epidemiology within a robust and computational efficient framework. The individual based model presented included an explicit spatial structure, vector and human movement, spatio-temporal heterogeneity in population densities, and climate effects. The flexibility of the framework allowed robust assessment of the implications of classical modelling assumptions on the basic reproduction number, R₀, demonstrating that traditional approaches grossly inflate R₀ estimates. The model's more realistic meta-population formulation was then exploited to elucidate the effects of ecological heterogeneities on dengue incidence which showed that sufficient levels of community connectivity are required for the spread and persistence of dengue virus. By fitting the individual based model to empirical data, the influence of climate and on dengue was quantified, revealing the strong benefits that cross-sectional serological data could bring to more precisely inferring ecological drivers of arboviral epidemiology. Overall, the findings presented here demonstrate the wide epidemiological landscape which ecological drivers induce, forewarning against the strong implications of generalising interpretations from one particular setting across wider spatial contexts. These findings will prove invaluable for the assessment of vector-borne control strategies, such as mosquito elimination or vaccination deployment programs.
Abstract.
2019
Talavera-López C, Bediako Y, Lin J-W, Joseph Valletta J, Recker M, Langhorne J (2019). Comparison of whole blood and spleen transcriptional signatures over the course of an experimental malaria infection.
Sci Rep,
9(1).
Abstract:
Comparison of whole blood and spleen transcriptional signatures over the course of an experimental malaria infection.
Although the spleen is broadly accepted as the major lymphoid organ involved in generating immune responses to the erythrocytic stages of the malaria parasite, Plasmodium, human splenic tissue is not readily available in most cases. As a result, most studies of malaria in humans rely on peripheral blood to assess cellular immune responses to malaria. The suitability of peripheral blood as a proxy for splenic immune responses is however unknown. Here, we have simultaneously analysed the transcriptomes of whole blood and spleen over 12 days of erythrocytic stage Plasmodium chabaudi infection in C57BL/6 mice. Using both unsupervised and directed approaches, we compared gene expression between blood and spleen over the course of infection. Taking advantage of publicly available datasets, we used machine learning approaches to infer cell proportions and cell-specific gene expression signatures from our whole tissue transcriptome data. Our findings demonstrate that spleen and blood are quite dissimilar, sharing only a small amount of transcriptional information between them, with transcriptional differences in both cellular composition and transcriptional activity. These results suggest that while blood transcriptome data may be useful in defining surrogate markers of protection and pathology, they should not be used to predict specific immune responses occurring in lymphoid organs.
Abstract.
Author URL.
Bediako Y, Adams R, Reid AJ, Valletta JJ, Ndungu FM, Sodenkamp J, Mwacharo J, Ngoi JM, Kimani D, Kai O, et al (2019). Repeated clinical malaria episodes are associated with modification of the immune system in children.
BMC Med,
17(1).
Abstract:
Repeated clinical malaria episodes are associated with modification of the immune system in children.
BACKGROUND: There are over 200 million reported cases of malaria each year, and most children living in endemic areas will experience multiple episodes of clinical disease before puberty. We set out to understand how frequent clinical malaria, which elicits a strong inflammatory response, affects the immune system and whether these modifications are observable in the absence of detectable parasitaemia. METHODS: We used a multi-dimensional approach comprising whole blood transcriptomic, cellular and plasma cytokine analyses on a cohort of children living with endemic malaria, but uninfected at sampling, who had been under active surveillance for malaria for 8 years. Children were categorised into two groups depending on the cumulative number of episodes experienced: high (≥ 8) or low (
Abstract.
Author URL.
Klumper U, Recker M, Zhang L, Yin X, Zhang T, Buckling A, Gaze W (2019). Selection for antimicrobial resistance is reduced when embedded in a natural microbial community. The ISME Journal
2018
Yokoyama M, Stevens E, Laabei M, Bacon L, Heesom K, Bayliss S, Ooi N, O'Neill AJ, Murray E, Williams P, et al (2018). Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA.
Genome Biology,
19(1).
Abstract:
Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA
Background: Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. The scale of these costs is highly variable. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. However, this is not supported by surveillance data in healthy communities, which indicate that this resistance mechanism is relatively unsuccessful. Results: Epistasis analysis on two collections of MRSA provides an explanation for this discord, where the mupirocin resistance-conferring mutation of the ileS gene appears to affect the levels of toxins produced by S. aureus when combined with specific polymorphisms at other loci. Proteomic analysis demonstrates that the activity of the secretory apparatus of the PSM family of toxins is affected by mupirocin resistance. As an energetically costly activity, this reduction in toxicity masks the fitness costs associated with this resistance mutation, a cost that becomes apparent when toxin production becomes necessary. This hidden fitness cost provides a likely explanation for why this mupirocin-resistance mechanism is not more prevalent, given the widespread use of this antibiotic. Conclusions: with dwindling pools of antibiotics available for use, information on the fitness consequences of the acquisition of resistance may need to be considered when designing antibiotic prescribing policies. However, this study suggests there are levels of depth that we do not understand, and that holistic, surveillance and functional genomics approaches are required to gain this crucial information.
Abstract.
Tennant W, Lourenco J, Faria N, Junior Alcantara L, Recker M (2018). INFLUENCE OF TEMPERATURE AND RAINFALL ON THE EPIDEMIOLOGY OF ARBOVIRAL DISEASES IN ENVIRONMENTALLY DISTINCTIVE REGIONS OF BRAZIL.
Author URL.
Bediako Y, Adams R, Reid A, Valletta J, Ndungu F, Mwacharo J, Ngoi J, Kimani D, Kai O, Wambua J, et al (2018). INVESTIGATING IMMUNE SIGNATURES IN MALARIA-EXPOSED CHILDREN.
Author URL.
Archer CR, Recker M, Duffy E, Hosken DJ (2018). Intralocus sexual conflict can resolve the male-female health-survival paradox.
Nature Communications,
9(1).
Abstract:
Intralocus sexual conflict can resolve the male-female health-survival paradox
At any given age, men are more likely to die than women, but women have poorer health at older ages. This is referred to as the “male-female, health-survival paradox”, which is not fully understood. Here, we provide a general solution to the paradox that relies on intralocus sexual conflict, where alleles segregating in the population have late-acting positive effects on male fitness, but negative effects on female health. Using an evolutionary modelling framework, we show that male-benefit, female-detriment alleles can spread if they are expressed after female reproduction stops. We provide support for our conflict based solution using experimental Drosophila data. Our results show that selecting for increased late-life male reproductive effort can increase male fitness but have a detrimental effect on female fitness. Furthermore, we show that late-life male fertility is negatively genetically correlated with female health. Our study suggests that intralocus sexual conflict could resolve the health-survival paradox.
Abstract.
Holding T, Valletta JJ, Recker M (2018). Multiscale immune selection and the transmission-diversity feedback in antigenically diverse pathogen systems.
American Naturalist,
192(6), E189-E201.
Abstract:
Multiscale immune selection and the transmission-diversity feedback in antigenically diverse pathogen systems
Antigenic diversity is commonly used by pathogens to enhance their transmission success. Within-host clonal antigenic variation helps to maintain long infectious periods, whereas high levels of allelic diversity at the population level significantly expand the pool of susceptible individuals. Diversity, however, is not necessarily a static property of a pathogen population but in many cases is generated by the very act of infection and transmission, and it is therefore expected to respond dynamically to changes in transmission and immune selection. We hypothesized that this coupling creates a positive feedback whereby infection and disease transmission promote the generation of diversity, which itself facilitates immune evasion and further infections. To investigate this link in more detail, we considered the human malaria parasite Plasmodium falciparum, one of the most important antigenically diverse pathogens. We developed an individual-based model in which antigenic diversity emerges as a dynamic property from the underlying transmission processes. Our results show that the balance between stochastic extinction and the generation of new antigenic variants is intrinsically linked to within-host and between-host immune selection. This in turn determines the level of diversity that can be maintained in a given population. Furthermore, the transmission-diversity feedback can lead to temporal lags in the response to natural or intervention-induced perturbations in transmission rates. Our results therefore have important implications for monitoring and assessing the effectiveness of disease control efforts.
Abstract.
Gates DE, Valletta JJ, Bonneaud C, Recker M (2018). Quantitative host resistance drives the evolution of increased virulence in an emerging pathogen.
J Evol Biol,
31(11), 1704-1714.
Abstract:
Quantitative host resistance drives the evolution of increased virulence in an emerging pathogen.
Emergent infectious diseases can have a devastating impact on host populations. The high selective pressures on both the hosts and the pathogens frequently lead to rapid adaptations not only in pathogen virulence but also host resistance following an initial outbreak. However, it is often unclear whether hosts will evolve to avoid infection-associated fitness costs by preventing the establishment of infection (here referred to as qualitative resistance) or by limiting its deleterious effects through immune functioning (here referred to as quantitative resistance). Equally, the evolutionary repercussions these different resistance mechanisms have for the pathogen are often unknown. Here, we investigate the co-evolutionary dynamics of pathogen virulence and host resistance following the epizootic outbreak of the highly pathogenic bacterium Mycoplasma gallisepticum in North American house finches (Haemorhous mexicanus). Using an evolutionary modelling approach and with a specific emphasis on the evolved resistance trait, we demonstrate that the rapid increase in the frequency of resistant birds following the outbreak is indicative of strong selection pressure to reduce infection-associated mortality. This, in turn, created the ecological conditions that selected for increased bacterial virulence. Our results thus suggest that quantitative host resistance was the key factor underlying the evolutionary interactions in this natural host-pathogen system.
Abstract.
Author URL.
Recker M, Bull P, Buckee C (2018). Recent advances in the molecular epidemiology of clinical malaria.
Abstract:
Recent advances in the molecular epidemiology of clinical malaria
Human malaria is a complex disease that can show a wide array of clinical outcomes, from asymptomatic carriage and chronic infection to acute disease presenting various life-threatening pathologies. The specific outcome of an infection is believed to be determined by a multifactorial interplay between the host and the parasite but with a general trend toward disease attenuation with increasing prior exposure. Therefore, the main burden of malaria in a population can be understood as a function of transmission intensity, which itself is intricately linked to the prevalence of infected hosts and mosquito vectors, the distribution of infection outcomes, and the parasite population diversity. Predicting the long-term impact of malaria intervention measures therefore requires an in-depth understanding of how the parasite causes disease, how this relates to previous exposures, and how different infection pathologies contribute to parasite transmission. Here, we provide a brief overview of recent advances in the molecular epidemiology of clinical malaria and how these might prove to be influential in our fight against this important disease.
Abstract.
Recker M, Buckee CO, Bull P (2018). Recent advances in the molecular epidemiology of clinical malaria. F1000Research
Tennant W, Recker M (2018). Robustness of the reproductive number estimates in vector-borne disease systems.
PLoS Neglected Tropical Diseases,
12(12).
Abstract:
Robustness of the reproductive number estimates in vector-borne disease systems
Background: the required efforts, feasibility and predicted success of an intervention strategy against an infectious disease are partially determined by its basic reproduction number, R 0. In its simplest form R 0 can be understood as the product of the infectious period, the number of infectious contacts and the per-contact transmission probability, which in the case of vector-transmitted diseases necessarily extend to the vector stages. As vectors do not usually recover from infection, they remain infectious for life, which places high significance on the vector’s life expectancy. Current methods for estimating the R 0 for a vector-borne disease are mostly derived from compartmental modelling frameworks assuming constant vector mortality rates. We hypothesised that some of the assumptions underlying these models can lead to unrealistic high vector life expectancies with important repercussions for R 0 estimates. Methodology and principal findings: Here we used a stochastic, individual-based model which allowed us to directly measure the number of secondary infections arising from one index case under different assumptions about vector mortality. Our results confirm that formulas based on age-independent mortality rates can overestimate R 0 by nearly 100% compared to our own estimate derived from first principles. We further provide a correction factor that can be used with a standard R 0 formula and adjusts for the discrepancies due to erroneous vector age distributions. Conclusion: Vector mortality rates play a crucial role for the success and general epidemiology of vector-transmitted diseases. Many modelling efforts intrinsically assume these to be age-independent, which, as clearly demonstrated here, can lead to severe over-estimation of the disease’s reproduction number. Our results thus re-emphasise the importance of obtaining field-relevant and species-dependent vector mortality rates, which in turn would facilitate more realistic intervention impact predictions.
Abstract.
2017
Valletta JJ, Lin J, Recker M, Langhorne J (2017). COMPARATIVE TRANSCRIPTOME ANALYSIS OF THE HOST RESPONSE IN BLOOD AND SPLEEN DURING THE COURSE OF a PLASMODIUM CHABAUDI CHABAUDI INFECTION.
Author URL.
Lourenço J, Tennant W, Faria NR, Walker A, Gupta S, Recker M (2017). Challenges in dengue research: a computational perspective. Evolutionary Applications, 11(4), 516-533.
Recker M, Laabei M, Toleman MS, Reuter S, Saunderson RB, Blane B, Török ME, Ouadi K, Stevens E, Yokoyama M, et al (2017). Clonal differences in Staphylococcus aureus bacteraemia-associated mortality.
Nat Microbiol,
2(10), 1381-1388.
Abstract:
Clonal differences in Staphylococcus aureus bacteraemia-associated mortality.
The bacterium Staphylococcus aureus is a major human pathogen for which the emergence of antibiotic resistance is a global public health concern. Infection severity, and in particular bacteraemia-associated mortality, has been attributed to several host-related factors, such as age and the presence of comorbidities. The role of the bacterium in infection severity is less well understood, as it is complicated by the multifaceted nature of bacterial virulence, which has so far prevented a robust mapping between genotype, phenotype and infection outcome. To investigate the role of bacterial factors in contributing to bacteraemia-associated mortality, we phenotyped a collection of sequenced clinical S. aureus isolates from patients with bloodstream infections, representing two globally important clonal types, CC22 and CC30. By adopting a genome-wide association study approach we identified and functionally verified several genetic loci that affect the expression of cytolytic toxicity and biofilm formation. By analysing the pooled data comprising bacterial genotype and phenotype together with clinical metadata within a machine-learning framework, we found significant clonal differences in the determinants most predictive of poor infection outcome. Whereas elevated cytolytic toxicity in combination with low levels of biofilm formation was predictive of an increased risk of mortality in infections by strains of a CC22 background, these virulence-specific factors had little influence on mortality rates associated with CC30 infections. Our results therefore suggest that different clones may have adopted different strategies to overcome host responses and cause severe pathology. Our study further demonstrates the use of a combined genomics and data analytic approach to enhance our understanding of bacterial pathogenesis at the individual level, which will be an important step towards personalized medicine and infectious disease management.
Abstract.
Author URL.
Tennant WS, Recker M (2017). EFFECTS OF COMMUNITY STRUCTURES AND ENVIRONMENTAL HETEROGENEITIES ON THE SPREAD AND PERSISTENCE OF DENGUE.
Author URL.
Lourenço J, de Lima MM, Faria N, Walker A, Kraemer M, Villabona-Arenas C, Lambert B, de Cerqueira EM, Pybus O, Alcantara L, et al (2017). Epidemiological and ecological determinants of Zika virus transmission in an urban setting.
Lourenço J, de Lima MM, Faria NR, Walker A, Kraemer MUG, Villabona-Arenas CJ, Lambert B, de Cerqueira EM, Pybus OG, Alcantara LCJ, et al (2017). Epidemiological and ecological determinants of Zika virus transmission in an urban setting.
eLife,
6Abstract:
Epidemiological and ecological determinants of Zika virus transmission in an urban setting
The Zika virus has emerged as a global public health concern. Its rapid geographic expansion is attributed to the success of Aedes mosquito vectors, but local epidemiological drivers are still poorly understood. Feira de Santana played a pivotal role in the Chikungunya epidemic in Brazil and was one of the first urban centres to report Zika infections. Using a climate-driven transmission model and notified Zika case data, we show that a low observation rate and high vectorial capacity translated into a significant attack rate during the 2015 outbreak, with a subsequent decline in 2016 and fade-out in 2017 due to herd-immunity. We find a potential Zika-related, low risk for microcephaly per pregnancy, but with significant public health impact given high attack rates. The balance between the loss of herd-immunity and viral re-importation will dictate future transmission potential of Zika in this urban setting.
Abstract.
Yokoyama M, Laabei M, Stevens E, Bacon L, Heesom K, Bayliss S, Ooi N, O’Neill AJ, Murray E, Williams P, et al (2017). Hidden antibiotic resistance fitness costs revealed by GWAS-based epistasis analysis.
Recker M, Valletta JJ (2017). IDENTIFICATION OF IMMUNE SIGNATURES UNDERLYING CLINICAL IMMUNITY TO PLASMODIUM FALCIPARUM MALARIA.
Author URL.
Valletta JJ, Recker M (2017). Identification of immune signatures predictive of clinical protection from malaria.
PLoS Comput Biol,
13(10).
Abstract:
Identification of immune signatures predictive of clinical protection from malaria.
Antibodies are thought to play an essential role in naturally acquired immunity to malaria. Prospective cohort studies have frequently shown how continuous exposure to the malaria parasite Plasmodium falciparum cause an accumulation of specific responses against various antigens that correlate with a decreased risk of clinical malaria episodes. However, small effect sizes and the often polymorphic nature of immunogenic parasite proteins make the robust identification of the true targets of protective immunity ambiguous. Furthermore, the degree of individual-level protection conferred by elevated responses to these antigens has not yet been explored. Here we applied a machine learning approach to identify immune signatures predictive of individual-level protection against clinical disease. We find that commonly assumed immune correlates are poor predictors of clinical protection in children. On the other hand, antibody profiles predictive of an individual's malaria protective status can be found in data comprising responses to a large set of diverse parasite proteins. We show that this pattern emerges only after years of continuous exposure to the malaria parasite, whereas susceptibility to clinical episodes in young hosts (< 10 years) cannot be ascertained by measured antibody responses alone.
Abstract.
Author URL.
Holding T, Recker M (2017). PLASMODIUM FALCIPARUM EPIDEMIOLOGY IS GOVERNED BY MULTI-SCALE IMMUNE SELECTION AND a DIVERSITY-TRANSMISSION FEEDBACK.
Author URL.
2016
Recker M, Vannice K, Hombach J, Jit M, Simmons CP (2016). Assessing dengue vaccination impact: Model challenges and future directions.
Vaccine,
34(38), 4461-4465.
Abstract:
Assessing dengue vaccination impact: Model challenges and future directions
In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk–benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making.
Abstract.
Lourenço J, Recker M (2016). Dengue serotype immune-interactions and their consequences for vaccine impact predictions.
Epidemics,
16, 40-48.
Abstract:
Dengue serotype immune-interactions and their consequences for vaccine impact predictions
Dengue is one of the most important and wide-spread viral infections affecting human populations. The last few decades have seen a dramatic increase in the global burden of dengue, with the virus now being endemic or near-endemic in over 100 countries world-wide. A recombinant tetravalent vaccine candidate (CYD-TDV) has recently completed Phase III clinical efficacy trials in South East Asia and Latin America and has been licensed for use in several countries. The trial results showed moderate-to-high efficacies in protection against clinical symptoms and hospitalisation but with so far unknown effects on transmission and infections per se. Model-based predictions about the vaccine's short- or long-term impact on the burden of dengue are therefore subject to a considerable degree of uncertainty. Furthermore, different immune interactions between dengue's serotypes have frequently been evoked by modelling studies to underlie dengue's oscillatory dynamics in disease incidence and serotype prevalence. Here we show how model assumptions regarding immune interactions in the form of antibody-dependent enhancement, temporary cross-immunity and the number of infections required to develop full immunity can significantly affect the predicted outcome of a dengue vaccination campaign. Our results thus re-emphasise the important gap in our current knowledge concerning the effects of previous exposure on subsequent dengue infections and further suggest that intervention impact studies should be critically evaluated by their underlying assumptions about serotype immune-interactions.
Abstract.
Recker M, Laabei M, Toleman MS, Reuter S, Blane B, Török E, Bayliss S, Peacock SJ, Massey RC (2016). Individual level predictions of Staphylococcus aureus bacteraemia-associated mortality.
Flasche S, Jit M, Rodríguez-Barraquer I, Coudeville L, Recker M, Koelle K, Milne G, Hladish TJ, Perkins TA, Cummings DAT, et al (2016). The Long-Term Safety, Public Health Impact, and Cost-Effectiveness of Routine Vaccination with a Recombinant, Live-Attenuated Dengue Vaccine (Dengvaxia): a Model Comparison Study.
PLoS Medicine,
13(11).
Abstract:
The Long-Term Safety, Public Health Impact, and Cost-Effectiveness of Routine Vaccination with a Recombinant, Live-Attenuated Dengue Vaccine (Dengvaxia): a Model Comparison Study
Background: Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine. Methods and Findings: the models adopted, with small variations, a parsimonious vaccine mode of action that was able to reproduce quantitative features of the observed trial data. The adopted mode of action assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections. The default vaccination policy considered was routine vaccination of 9-y-old children in a three-dose schedule at 80% coverage. The outcomes examined were the impact of vaccination on infections, symptomatic dengue, hospitalised dengue, deaths, and cost-effectiveness over a 30-y postvaccination period. Case definitions were chosen in accordance with the Phase III trials. All models predicted that in settings with moderate to high dengue endemicity (SP9 ≥ 50%), the default vaccination policy would reduce the burden of dengue disease for the population by 6%–25% (all simulations: –3%–34%) and in high-transmission settings (SP9 ≥ 70%) by 13%–25% (all simulations: 10%– 34%). These endemicity levels are representative of the participating sites in both Phase III trials. In contrast, in settings with low transmission intensity (SP9 ≤ 30%), the models predicted that vaccination could lead to a substantial increase in hospitalisation because of dengue. Modelling reduced vaccine coverage or the addition of catch-up campaigns showed that the impact of vaccination scaled approximately linearly with the number of people vaccinated. In assessing the optimal age of vaccination, we found that targeting older children could increase the net benefit of vaccination in settings with moderate transmission intensity (SP9 = 50%). Overall, vaccination was predicted to be potentially cost-effective in most endemic settings if priced competitively. The results are based on the assumption that the vaccine acts similarly to natural infection. This assumption is consistent with the available trial results but cannot be directly validated in the absence of additional data. Furthermore, uncertainties remain regarding the level of protection provided against disease versus infection and the rate at which vaccine-induced protection declines. Conclusions: Dengvaxia has the potential to reduce the burden of dengue disease in areas of moderate to high dengue endemicity. However, the potential risks of vaccination in areas with limited exposure to dengue as well as the local costs and benefits of routine vaccination are important considerations for the inclusion of Dengvaxia into existing immunisation programmes. These results were important inputs into WHO global policy for use of this licensed dengue vaccine.
Abstract.
2015
Laabei M, Uhlemann AC, Lowy FD, Austin ED, Yokoyama M, Ouadi K, Feil E, Thorpe HA, Williams B, Perkins M, et al (2015). Evolutionary Trade-Offs Underlie the Multi-faceted Virulence of Staphylococcus aureus.
PLoS Biology,
13(9).
Abstract:
Evolutionary Trade-Offs Underlie the Multi-faceted Virulence of Staphylococcus aureus
Bacterial virulence is a multifaceted trait where the interactions between pathogen and host factors affect the severity and outcome of the infection. Toxin secretion is central to the biology of many bacterial pathogens and is widely accepted as playing a crucial role in disease pathology. To understand the relationship between toxicity and bacterial virulence in greater depth, we studied two sequenced collections of the major human pathogen Staphylococcus aureus and found an unexpected inverse correlation between bacterial toxicity and disease severity. By applying a functional genomics approach, we identified several novel toxicity-affecting loci responsible for the wide range in toxic phenotypes observed within these collections. To understand the apparent higher propensity of low toxicity isolates to cause bacteraemia, we performed several functional assays, and our findings suggest that within-host fitness differences between high- and low-toxicity isolates in human serum is a contributing factor. As invasive infections, such as bacteraemia, limit the opportunities for onward transmission, highly toxic strains could gain an additional between-host fitness advantage, potentially contributing to the maintenance of toxicity at the population level. Our results clearly demonstrate how evolutionary trade-offs between toxicity, relative fitness, and transmissibility are critical for understanding the multifaceted nature of bacterial virulence.
Abstract.
Holding T, Recker M (2015). Maintenance of phenotypic diversity within a set of virulence encoding genes of the malaria parasite Plasmodium falciparum.
Journal of the Royal Society Interface,
12(113).
Abstract:
Maintenance of phenotypic diversity within a set of virulence encoding genes of the malaria parasite Plasmodium falciparum
Infection by the human malaria parasite Plasmodium falciparum results in a broad spectrum of clinical outcomes, ranging from severe and potentially life-threatening malaria to asymptomatic carriage. In a process of naturally acquired immunity, individuals living in malaria-endemic regions build up a level of clinical protection, which attenuates infection severity in an exposure-dependent manner. Underlying this shift in the immunoepidemiology aswell as the observed range in malaria pathogenesis is the var multigene family and the phenotypic diversity embedded within. The var gene-encoded surface proteins Plasmodium falciparum erythrocyte membrane protein 1 mediate variant-specific binding of infected red blood cells to a diverse set of host receptors that has been linked to specific disease manifestations, including cerebral and pregnancy-associated malaria. Here,we showthat cross-reactive immune responses, which minimize the within-host benefit of each additionally expressed gene during infection, can cause selection for maximum phenotypic diversity at the genome level. We further show that differential functional constraints on protein diversification stably maintain uneven ratios between phenotypic groups, in line with empirical observation. Our results thus suggest that the maintenance of phenotypic diversity within P. falciparum is driven by an evolutionary trade-off that optimizes between within-host parasite fitness and between-host selection pressure.
Abstract.
2014
Laabei M, Recker M, Rudkin JK, Aldeljawi M, Gulay Z, Sloan TJ, Williams P, Endres JL, Bayles KW, Fey PD, et al (2014). Predicting the virulence of MRSA from its genome sequence.
Genome Research,
24(5), 839-849.
Abstract:
Predicting the virulence of MRSA from its genome sequence
Microbial virulence is a complex and often multifactorial phenotype, intricately linked to a pathogen's evolutionary trajectory. Toxicity, the ability to destroy host cell membranes, and adhesion, the ability to adhere to human tissues, are the major virulence factors of many bacterial pathogens, including Staphylococcus aureus. Here, we assayed the toxicity and adhesiveness of 90 MRSA (methicillin resistant S. aureus) isolates and found that while there was remarkably little variation in adhesion, toxicity varied by over an order of magnitude between isolates, suggesting different evolutionary selection pressures acting on these two traits. We performed a genome-wide association study (GWAS) and identified a large number of loci, as well as a putative network of epistatically interacting loci, that significantly associated with toxicity. Despite this apparent complexity in toxicity regulation, a predictive model based on a set of significant single nucleotide polymorphisms (SNPs) and insertion and deletions events (indels) showed a high degree of accuracy in predicting an isolate's toxicity solely from the genetic signature at these sites.Our results thus highlight the potential of using sequence data to determine clinically relevant parameters and have further implications for understanding the microbial virulence of this opportunistic pathogen. © 2014 Nagarajan et al.
Abstract.
Heiny SR, Pautz S, Recker M, Przyborski JM (2014). Protein traffic to the plasmodium falciparum apicoplast: Evidence for a sorting branch point at the Golgi.
Traffic,
15(12), 1290-1304.
Abstract:
Protein traffic to the plasmodium falciparum apicoplast: Evidence for a sorting branch point at the Golgi
Plasmodium falciparum, similar to many other apicomplexan parasites, contains an apicoplast, a plastid organelle of secondary endosymbiotic origin. Nuclear-encoded proteins are posttranslationally transported to the apicoplast via the endoplasmic reticulum. However, it has long been a matter of contention if the Golgi also plays a role in this process. In this study, we show that trafficking to the apicoplast occurs via the Golgi as an intermediate compartment. Our data suggest that the Plasmodium Golgi has an important function as a protein sorting compartment. Plasmodium falciparum, similar to many other apicomplexan parasites, contains an apicoplast, a plastid organelle of secondary endosymbiotic origin. Nuclear-encoded proteins are targeted to the apicoplast by a bipartite topogenic signal consisting of (i) an endoplasmic reticulum (ER)-type N-terminal secretory signal peptide, followed by (ii) a plant-like transit peptide. Although the signals responsible for transport of most proteins to the apicoplast are well described, the route of trafficking from the ER to the outermost apicoplast membrane is still a matter of debate. Current models of trafficking to the apicoplast suggest that proteins destined for this organelle are, on entry into the lumen of the ER, diverted from the default secretory pathway to a specialized vesicular system which carries proteins directly from the ER to the outer apicoplast membrane. Here, we have re-examined this trafficking pathway. By titrating wild-type and mutant apicoplast transit peptides against different ER retrieval sequences and studying protein transport in a brefeldin A-resistant parasite line, we generated data which suggest a direct involvement of the Golgi in traffic of soluble proteins to the P. falciparum apicoplast.
Abstract.
Lourenço J, Recker M (2014). The 2012 Madeira dengue outbreak: epidemiological determinants and future epidemic potential.
PLoS Negl Trop Dis,
8(8).
Abstract:
The 2012 Madeira dengue outbreak: epidemiological determinants and future epidemic potential.
Dengue, a vector-borne viral disease of increasing global importance, is classically associated with tropical and sub-tropical regions around the world. Urbanisation, globalisation and climate trends, however, are facilitating the geographic spread of its mosquito vectors, thereby increasing the risk of the virus establishing itself in previously unaffected areas and causing large-scale epidemics. On 3 October 2012, two autochthonous dengue infections were reported within the Autonomous Region of Madeira, Portugal. During the following seven months, this first 'European' dengue outbreak caused more than 2000 local cases and 81 exported cases to mainland Europe. Here, using an ento-epidemiological mathematical framework, we estimate that the introduction of dengue to Madeira occurred around a month before the first official cases, during the period of maximum influx of airline travel, and that the naturally declining temperatures of autumn were the determining factor for the outbreak's demise in early December 2012. Using key estimates, together with local climate data, we further propose that there is little support for dengue endemicity on this island, but a high potential for future epidemic outbreaks when seeded between May and August-a period when detection of imported cases is crucial for Madeira's public health planning.
Abstract.
Author URL.
2013
Lourenço J, Recker M (2013). Natural, persistent oscillations in a spatial multi-strain disease system with application to dengue.
PLoS computational biology,
9(10).
Abstract:
Natural, persistent oscillations in a spatial multi-strain disease system with application to dengue.
Many infectious diseases are not maintained in a state of equilibrium but exhibit significant fluctuations in prevalence over time. For pathogens that consist of multiple antigenic types or strains, such as influenza, malaria or dengue, these fluctuations often take on the form of regular or irregular epidemic outbreaks in addition to oscillatory prevalence levels of the constituent strains. To explain the observed temporal dynamics and structuring in pathogen populations, epidemiological multi-strain models have commonly evoked strong immune interactions between strains as the predominant driver. Here, with specific reference to dengue, we show how spatially explicit, multi-strain systems can exhibit all of the described epidemiological dynamics even in the absence of immune competition. Instead, amplification of natural stochastic differences in disease transmission, can give rise to persistent oscillations comprising semi-regular epidemic outbreaks and sequential dominance of dengue's four serotypes. Not only can this mechanism explain observed differences in serotype and disease distributions between neighbouring geographical areas, it also has important implications for inferring the nature and epidemiological consequences of immune mediated competition in multi-strain pathogen systems.
Abstract.
Warimwe GM, Recker M, Kiragu EW, Buckee CO, Wambua J, Musyoki JN, Marsh K, Bull PC (2013). Plasmodium falciparum var Gene Expression Homogeneity as a Marker of the Host-Parasite Relationship under Different Levels of Naturally Acquired Immunity to Malaria.
PLoS ONE,
8(7).
Abstract:
Plasmodium falciparum var Gene Expression Homogeneity as a Marker of the Host-Parasite Relationship under Different Levels of Naturally Acquired Immunity to Malaria
Acquired immunity to Plasmodium falciparum infection causes a change from frequent, sometimes life-threatening, malaria in young children to asymptomatic, chronic infections in older children and adults. Little is known about how this transition occurs but antibodies to the extremely diverse PfEMP1 parasite antigens are thought to play a role. PfEMP1 is encoded by a family of 60 var genes that undergo clonal antigenic variation, potentially creating an antigenically heterogeneous infecting population of parasites within the host. Previous theoretical work suggests that antibodies to PfEMP1 may play a role in "orchestrating" their expression within infections leading to sequential, homogeneous expression of var genes, and prolonged infection chronicity. Here, using a cloning and sequencing approach we compare the var expression homogeneity (VEH) between isolates from children with asymptomatic and clinical infections. We show that asymptomatic infections have higher VEH than clinical infections and a broader host antibody response. We discuss this in relation to the potential role of host antibodies in promoting chronicity of infection and parasite survival through the low transmission season. © 2013 Warimwe et al.
Abstract.
Wikramaratna PS, Sandeman M, Recker M, Gupta S (2013). The antigenic evolution of influenza: Drift or thrift?.
Philosophical Transactions of the Royal Society B: Biological Sciences,
368(1614).
Abstract:
The antigenic evolution of influenza: Drift or thrift?
It is commonly assumed that antibody responses against the influenza virus are polarized in the following manner: strong antibody responses are directed at highly variable antigenic epitopes, which consequently undergo 'antigenic drift', while weak antibody responses develop against conserved epitopes. As the highly variable epitopes are in a constant state of flux, current antibody-based vaccine strategies are focused on the conserved epitopes in the expectation that they will provide some level of clinical protection after appropriate boosting. Here, we use a theoretical model to suggest the existence of epitopes of low variability, which elicit a high degree of both clinical and transmission-blocking immunity. We show that several epidemiological features of influenza and its serological and molecular profiles are consistent with this model of 'antigenic thrift', and that identifying the protective epitopes of low variability predicted by this model could offer a more viable alternative to regularly update the influenza vaccine than exploiting responses to weakly immunogenic conserved regions. © 2013 the Author(s) Published by the Royal Society. All rights reserved.
Abstract.
Wikramaratna PS, Sandeman M, Recker M, Gupta S (2013). The antigenic evolution of influenza: drift or thrift?.
Philos Trans R Soc Lond B Biol Sci,
368(1614).
Abstract:
The antigenic evolution of influenza: drift or thrift?
It is commonly assumed that antibody responses against the influenza virus are polarized in the following manner: strong antibody responses are directed at highly variable antigenic epitopes, which consequently undergo 'antigenic drift', while weak antibody responses develop against conserved epitopes. As the highly variable epitopes are in a constant state of flux, current antibody-based vaccine strategies are focused on the conserved epitopes in the expectation that they will provide some level of clinical protection after appropriate boosting. Here, we use a theoretical model to suggest the existence of epitopes of low variability, which elicit a high degree of both clinical and transmission-blocking immunity. We show that several epidemiological features of influenza and its serological and molecular profiles are consistent with this model of 'antigenic thrift', and that identifying the protective epitopes of low variability predicted by this model could offer a more viable alternative to regularly update the influenza vaccine than exploiting responses to weakly immunogenic conserved regions.
Abstract.
Author URL.
Noble R, Christodoulou Z, Kyes S, Pinches R, Newbold CI, Recker M (2013). The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria.
Elife,
2Abstract:
The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria.
Antigenic variation in the human malaria parasite Plasmodium falciparum involves sequential and mutually exclusive expression of members of the var multi-gene family and appears to follow a non-random pattern. In this study, using a detailed in vitro gene transcription analysis of the culture-adapted HB3 strain of P. falciparum, we show that antigenic switching is governed by a global activation hierarchy favouring short and highly diverse genes in central chromosomal location. Longer and more conserved genes, which have previously been associated with severe infection in immunologically naive hosts, are rarely activated, however, implying an in vivo fitness advantage possibly through adhesion-dependent survival rates. We further show that a gene's activation rate is positively associated sequence diversity, which could offer important new insights into the evolution and maintenance of antigenic diversity in P. falciparum malaria. DOI:http://dx.doi.org/10.7554/eLife.01074.001.
Abstract.
Author URL.
2012
Noble R, Recker M (2012). A statistically rigorous method for determining antigenic switching networks.
PLoS One,
7(6).
Abstract:
A statistically rigorous method for determining antigenic switching networks.
Many vector-borne pathogens rely on antigenic variation to prolong infections and increase their likelihood of onward transmission. This immune evasion strategy often involves mutually exclusive switching between members of gene families that encode functionally similar but antigenically different variants during the course of a single infection. Studies of different pathogens have suggested that switching between variant genes is non-random and that genes have intrinsic probabilities of being activated or silenced. These factors could create a hierarchy of gene expression with important implications for both infection dynamics and the acquisition of protective immunity. Inferring complete switching networks from gene transcription data is problematic, however, because of the high dimensionality of the system and uncertainty in the data. Here we present a statistically rigorous method for analysing temporal gene transcription data to reconstruct an underlying switching network. Using artificially generated transcription profiles together with in vitro var gene transcript data from two Plasmodium falciparum laboratory strains, we show that instead of relying on data from long-term parasite cultures, accuracy can be greatly improved by using transcription time courses of several parasite populations from the same isolate, each starting with different variant distributions. The method further provides explicit indications about the reliability of the resulting networks and can thus be used to test competing hypotheses with regards to the underlying switching pathways. Our results demonstrate that antigenic switch pathways can be determined reliably from short gene transcription profiles assessing multiple time points, even when subject to moderate levels of experimental error. This should yield important new information about switching patterns in antigenically variable organisms and might help to shed light on the molecular basis of antigenic variation.
Abstract.
Author URL.
Beatty M, Boni MF, Brown S, Buathong R, Burke D, Coudeville L, Cummings DAT, Edelman R, Farrar J, Focks DA, et al (2012). Assessing the Potential of a Candidate Dengue Vaccine with Mathematical Modeling.
PLOS NEGLECTED TROPICAL DISEASES,
6(3).
Author URL.
Fastman Y, Noble R, Recker M, Dzikowski R (2012). Erasing the epigenetic memory and beginning to switch-the onset of antigenic switching of var genes in plasmodium falciparum.
PLoS ONE,
7(3).
Abstract:
Erasing the epigenetic memory and beginning to switch-the onset of antigenic switching of var genes in plasmodium falciparum
Antigenic variation in Plasmodium falciparum is regulated by transcriptional switches among members of the var gene family, each expressed in a mutually exclusive manner and encoding a different variant of the surface antigens collectively named PfEMP1. Antigenic switching starts when the first merozoites egress from the liver and begin their asexual proliferation within red blood cells. By erasing the epigenetic memory we created parasites with no var background, similar to merozoites that egress from the liver where no var gene is expressed. Creating a null-var background enabled us to investigate the onset of antigenic switches at the early phase of infection. At the onset of switching, var transcription pattern is heterogeneous with numerous genes transcribed at low levels including upsA vars, a subtype that was implicated in severe malaria, which are rarely activated in growing cultures. Analysis of subsequent in vitro switches shows that the probability of a gene to turn on or off is not associated with its chromosomal position or promoter type per se but on intrinsic properties of each gene. We concluded that var switching is determined by gene specific associated switch rates rather than general promoter type or locus associated switch rates. In addition, we show that fine tuned reduction in var transcription increases their switch rate, indicating that transcriptional perturbation can alter antigenic switching. © 2012 Fastman et al.
Abstract.
Buckee CO, Recker M (2012). Evolution of the multi-domain structures of virulence genes in the human malaria parasite, Plasmodium falciparum.
PLoS Computational Biology,
8(4).
Abstract:
Evolution of the multi-domain structures of virulence genes in the human malaria parasite, Plasmodium falciparum
The var gene family of Plasmodium falciparum encodes the immunodominant variant surface antigens PfEMP1. These highly polymorphic proteins are important virulence factors that mediate cytoadhesion to a variety of host tissues, causing sequestration of parasitized red blood cells in vital organs, including the brain or placenta. Acquisition of variant-specific antibodies correlates with protection against severe malarial infections; however, understanding the relationship between gene expression and infection outcome is complicated by the modular genetic architectures of var genes that encode varying numbers of antigenic domains with differential binding specificities. By analyzing the domain architectures of fully sequenced var gene repertoires we reveal a significant, non-random association between the number of domains comprising a var gene and their sequence conservation. As such, var genes can be grouped into those that are short and diverse and genes that are long and conserved, suggesting gene length as an important characteristic in the classification of var genes. We then use an evolutionary framework to demonstrate how the same evolutionary forces acting on the level of an individual gene may have also shaped the parasite's gene repertoire. The observed associations between sequence conservation, gene architecture and repertoire structure can thus be explained by a trade-off between optimizing within-host fitness and minimizing between-host immune selection pressure. Our results demonstrate how simple evolutionary mechanisms can explain var gene structuring on multiple levels and have important implications for understanding the multifaceted epidemiology of P. falciparum malaria. © 2012 Buckee, Recker.
Abstract.
Priest NK, Rudkin JK, Feil EJ, Van Den Elsen JMH, Cheung A, Peacock SJ, Laabei M, Lucks DA, Recker M, Massey RC, et al (2012). From genotype to phenotype: can systems biology be used to predict Staphylococcus aureus virulence.
Nature Reviews Microbiology,
10(11), 791-797.
Abstract:
From genotype to phenotype: can systems biology be used to predict Staphylococcus aureus virulence
With the advent of high-throughput whole-genome sequencing, it is now possible to sequence a bacterial genome in a matter of hours. However, although the presence or absence of a particular gene can be determined, we do not yet have the tools to extract information about the true virulence potential of an organism from sequence data alone. Here, we focus on the important human pathogen Staphylococcus aureus and present a framework for the construction of a broad systems biology-based tool that could be used to predict virulence phenotypes from S. aureus genomic sequences using existing technology. © 2012 Macmillan Publishers Limited. All rights reserved.
Abstract.
2011
Recker M, Buckee CO, Serazin A, Kyes S, Pinches R, Christodoulou Z, Springer AL, Gupta S, Newbold CI (2011). Antigenic variation in Plasmodium falciparum malaria involves a highly structured switching pattern.
PLoS Pathog,
7(3).
Abstract:
Antigenic variation in Plasmodium falciparum malaria involves a highly structured switching pattern.
Many pathogenic bacteria, fungi, and protozoa achieve chronic infection through an immune evasion strategy known as antigenic variation. In the human malaria parasite Plasmodium falciparum, this involves transcriptional switching among members of the var gene family, causing parasites with different antigenic and phenotypic characteristics to appear at different times within a population. Here we use a genome-wide approach to explore this process in vitro within a set of cloned parasite populations. Our analyses reveal a non-random, highly structured switch pathway where an initially dominant transcript switches via a set of switch-intermediates either to a new dominant transcript, or back to the original. We show that this specific pathway can arise through an evolutionary conflict in which the pathogen has to optimise between safeguarding its limited antigenic repertoire and remaining capable of establishing infections in non-naïve individuals. Our results thus demonstrate a crucial role for structured switching during the early phases of infections and provide a unifying theory of antigenic variation in P. falciparum malaria as a balanced process of parasite-intrinsic switching and immune-mediated selection.
Abstract.
Author URL.
Portugal S, Carret C, Recker M, Armitage AE, Gonçalves LA, Epiphanio S, Sullivan D, Roy C, Newbold CI, Drakesmith H, et al (2011). Host-mediated regulation of superinfection in malaria.
Nature Medicine,
17(6), 732-737.
Abstract:
Host-mediated regulation of superinfection in malaria
In regions of high rates of malaria transmission, mosquitoes repeatedly transmit liver-tropic Plasmodium sporozoites to individuals who already have blood-stage parasitemia. This manifests itself in semi-immune children (who have been exposed since birth to Plasmodium infection and as such show low levels of peripheral parasitemia but can still be infected) older than 5 years of age by concurrent carriage of different parasite genotypes at low asymptomatic parasitemias. Superinfection presents an increased risk of hyperparasitemia and death in less immune individuals but counterintuitively is not frequently observed in the young. Here we show in a mouse model that ongoing blood-stage infections, above a minimum threshold, impair the growth of subsequently inoculated sporozoites such that they become growth arrested in liver hepatocytes and fail to develop into blood-stage parasites. Inhibition of the liver-stage infection is mediated by the host iron regulatory hormone hepcidin, whose synthesis we found to be stimulated by blood-stage parasites in a density-dependent manner. We mathematically modeled this phenomenon and show how density-dependent protection against liver-stage malaria can shape the epidemiological patterns of age-related risk and the complexity of malaria infections seen in young children. The interaction between these two Plasmodium stages and host iron metabolism has relevance for the global efforts to reduce malaria transmission and for evaluation of iron supplementation programs in malaria-endemic regions. © 2011 Nature America, Inc. All rights reserved.
Abstract.
Buckee CO, Recker M, Watkins ER, Gupta S (2011). Role of stochastic processes in maintaining discrete strain structure in antigenically diverse pathogen populations.
Proc Natl Acad Sci U S A,
108(37), 15504-15509.
Abstract:
Role of stochastic processes in maintaining discrete strain structure in antigenically diverse pathogen populations.
Many highly diverse pathogen populations appear to exist stably as discrete antigenic types despite evidence of genetic exchange. It has been shown that this may arise as a consequence of immune selection on pathogen populations, causing them to segregate permanently into discrete nonoverlapping subsets of antigenic variants to minimize competition for available hosts. However, discrete antigenic strain structure tends to break down under conditions where there are unequal numbers of allelic variants at each locus. Here, we show that the inclusion of stochastic processes can lead to the stable recovery of discrete strain structure through loss of certain alleles. This explains how pathogen populations may continue to behave as independently transmitted strains despite inevitable asymmetries in allelic diversity of major antigens. We present evidence for this type of structuring across global meningococcal isolates in three diverse antigens that are currently being developed as vaccine components.
Abstract.
Author URL.
2010
Collins J, Rudkin J, Recker M, Pozzi C, O'Gara JP, Massey RC (2010). Offsetting virulence and antibiotic resistance costs by MRSA.
ISME J,
4(4), 577-584.
Abstract:
Offsetting virulence and antibiotic resistance costs by MRSA.
The prevalence of diverse MRSA (methicillin-resistant Staphylococcus aureus) types in both hospital and community settings is a major health problem worldwide. Here we compare hospital-acquired MRSAs with large type II SCCmec elements with those prevalent in both hospital and community settings with smaller type IV SCCmec elements. We find that the type II but not the type IV SCCmec element causes the bacteria to reduce their levels of costly toxin expression. We compare the relative growth rates of these MRSA types and show that the type II SCCmec carrying MRSAs are more affected than those carrying type IV elements and from this we hypothesize that offsetting the costs associated with antibiotic resistance and toxin expression is why the type II are confined to hospital environments where antibiotic use, the prevalence of immunocompromised individuals and vector-mediated transmission is high. In contrast, those MRSAs that are also successful in the community can maintain their high levels of toxin expression due to a lower fitness burden associated with the smaller SCCmec element.
Abstract.
Author URL.
Wikramaratna PS, Simmons CP, Gupta S, Recker M (2010). The effects of tertiary and quaternary infections on the epidemiology of dengue.
PLoS One,
5(8).
Abstract:
The effects of tertiary and quaternary infections on the epidemiology of dengue.
The epidemiology of dengue is characterised by irregular epidemic outbreaks and desynchronised dynamics of its four co-circulating virus serotypes. Whilst infection by one serotype appears to convey life-long protection to homologous infection, it is believed to be a risk factor for severe disease manifestations upon secondary, heterologous infection due to the phenomenon of Antibody-Dependent Enhancement (ADE). Subsequent clinical infections are rarely reported and, since the majority of dengue infections are generally asymptomatic, it is not clear if and to what degree tertiary or quaternary infections contribute to dengue epidemiology. Here we investigate the effect of third and subsequent infections on the transmission dynamics of dengue and show that although the qualitative patterns are largely equivalent, the system more readily exhibits the desynchronised serotype oscillations and multi-annual epidemic outbreaks upon their inclusion. More importantly, permitting third and fourth infections significantly increases the force of infection without resorting to high basic reproductive numbers. Realistic age-prevalent patterns and seroconversion rates are therefore easier reconciled with a low value of dengue's transmission potential if allowing for more than two infections; this should have important consequences for dengue control and intervention measures.
Abstract.
Author URL.
Kiss IZ, Cassell J, Recker M, Simon PL (2010). The impact of information transmission on epidemic outbreaks.
Mathematical Biosciences,
225(1), 1-10.
Abstract:
The impact of information transmission on epidemic outbreaks
For many diseases (e.g. sexually transmitted infections, STIs), most individuals are aware of the potential risks of becoming infected, but choose not to take action ('respond') despite the information that aims to raise awareness and to increases the responsiveness or alertness of the population. We propose a simple mathematical model that accounts for the diffusion of health information disseminated as a result of the presence of a disease and an 'active' host population that can respond to it by taking measures to avoid infection or if infected by seeking treatment early. In this model, we assume that the whole population is potentially aware of the risk but only a certain proportion chooses to respond appropriately by trying to limit their probability of becoming infectious or seeking treatment early. The model also incorporates a level of responsiveness that decays over time. We show that if the dissemination of information is fast enough, infection can be eradicated. When this is not possible, information transmission has an important effect in reducing the prevalence of the infection. We derive the full characterisation of the global behaviour of the model, and we show that the parameter space can be divided into three parts according to the global attractor of the system which is one of the two disease-free steady states or the endemic equilibrium. © 2010.
Abstract.
Lourenço J, Recker M (2010). Viral and epidemiological determinants of the invasion dynamics of novel dengue genotypes.
PLoS Negl Trop Dis,
4(11).
Abstract:
Viral and epidemiological determinants of the invasion dynamics of novel dengue genotypes.
BACKGROUND: Dengue has become a major concern for international public health. Frequent epidemic outbreaks are believed to be driven by a complex interplay of immunological interactions between its four co-circulating serotypes and large fluctuations in mosquito densities. Viral lineage replacement events, caused for example by different levels of cross-protection or differences in viral fitness, have also been linked to a temporary change in dengue epidemiology. A major replacement event was recently described for South-East Asia where the Asian-1 genotype of dengue serotype 2 replaced the resident Asian/American type. Although this was proposed to be due to increased viral fitness in terms of enhanced human-to-mosquito transmission, no major change in dengue epidemiology could be observed. METHODS/RESULTS: Here we investigate the invasion dynamics of a novel, advantageous dengue genotype within a model system and determine the factors influencing the success and rate of fixation as well as their epidemiological consequences. We find that while viral fitness overall correlates with invasion success and competitive exclusion of the resident genotype, the epidemiological landscape plays a more significant role for successful emergence. Novel genotypes can thus face high risks of stochastic extinction despite their fitness advantage if they get introduced during episodes of high dengue prevalence, especially with respect to that particular serotype. CONCLUSION: the rarity of markers for positive selection has often been explained by strong purifying selection whereby the constraints imposed by dengue's two-host cycle are expected to result in a high rate of deleterious mutations. Our results demonstrate that even highly beneficial mutants are under severe threat of extinction, which would suggest that apart from purifying selection, stochastic effects and genetic drift beyond seasonal bottlenecks are equally important in shaping dengue's viral ecology and evolution.
Abstract.
Author URL.
2009
Recker M, Bouma MJ, Bamford P, Gupta S, Dobson AP (2009). Assessing the burden of pregnancy-associated malaria under changing transmission settings.
Malar J,
8Abstract:
Assessing the burden of pregnancy-associated malaria under changing transmission settings.
BACKGROUND: the clinical presentation of pregnancy-associated malaria, or PAM, depends crucially on the particular epidemiological settings. This can potentially lead to an underestimation of its overall burden on the female population, especially in regions prone to epidemic outbreaks and where malaria transmission is generally low. METHODS: Here, by re-examining historical data, it is demonstrated how excess female mortality can be used to evaluate the burden of PAM. A simple mathematical model is then developed to highlight the contrasting signatures of PAM within the endemicity spectrum and to show how PAM is influenced by the intensity and stability of transmission. RESULTS: Both the data and the model show that maternal malaria has a huge impact on the female population. This is particularly pronounced in low-transmission settings during epidemic outbreaks where excess female mortality/morbidity can by far exceed that of a similar endemic setting. CONCLUSION: the results presented here call for active intervention measures not only in highly endemic regions but also, or in particular, in areas where malaria transmission is low and seasonal.
Abstract.
Author URL.
Recker M, Blyuss KB, Simmons CP, Hien TT, Wills B, Farrar J, Gupta S (2009). Immunological serotype interactions and their effect on the epidemiological pattern of dengue.
Proc Biol Sci,
276(1667), 2541-2548.
Abstract:
Immunological serotype interactions and their effect on the epidemiological pattern of dengue.
Long-term epidemiological data reveal multi-annual fluctuations in the incidence of dengue fever and dengue haemorrhagic fever, as well as complex cyclical behaviour in the dynamics of the four serotypes of the dengue virus. It has previously been proposed that these patterns are due to the phenomenon of the so-called antibody-dependent enhancement (ADE) among dengue serotypes, whereby viral replication is increased during secondary infection with a heterologous serotype; however, recent studies have implied that this positive reinforcement cannot account for the temporal patterns of dengue and that some form of cross-immunity or external forcing is necessary. Here, we show that ADE alone can produce the observed periodicities and desynchronized oscillations of individual serotypes if its effects are decomposed into its two possible manifestations: enhancement of susceptibility to secondary infections and increased transmissibility from individuals suffering from secondary infections. This decomposition not only lowers the level of enhancement necessary for realistic disease patterns but also reduces the risk of stochastic extinction. Furthermore, our analyses reveal a time-lagged correlation between serotype dynamics and disease incidence rates, which could have important implications for understanding the irregular pattern of dengue epidemics.
Abstract.
Author URL.
2008
Buckee CO, Jolley KA, Recker M, Penman B, Kriz P, Gupta S, Maiden MCJ (2008). Role of selection in the emergence of lineages and the evolution of virulence in Neisseria meningitidis.
Proc Natl Acad Sci U S A,
105(39), 15082-15087.
Abstract:
Role of selection in the emergence of lineages and the evolution of virulence in Neisseria meningitidis.
Neisseria meningitis is a human commensal bacterium that occasionally causes life-threatening disease. As with a number of other bacterial pathogens, meningococcal populations comprise distinct lineages, which persist over many decades and during global spread in the face of high rates of recombination. In addition, the propensity to cause invasive disease is associated with particular "hyperinvasive" lineages that coexist with less invasive lineages despite the fact that disease does not contribute to host-to-host transmission. Here, by combining a modeling approach with molecular epidemiological data from 1,108 meningococci isolated in the Czech Republic over 27 years, we show that interstrain competition, mediated by immune selection, can explain both the persistence of multiple discrete meningococcal lineages and the association of a subset of these with invasive disease. The model indicates that the combinations of allelic variants of housekeeping genes that define these lineages are associated with very small differences in transmission efficiency among hosts. These findings have general implications for the emergence of lineage structure and virulence in recombining bacterial populations.
Abstract.
Author URL.
Recker M, Arinaminpathy N, Buckee CO (2008). The effects of a partitioned var gene repertoire of Plasmodium falciparum on antigenic diversity and the acquisition of clinical immunity.
Malar J,
7Abstract:
The effects of a partitioned var gene repertoire of Plasmodium falciparum on antigenic diversity and the acquisition of clinical immunity.
BACKGROUND: the human malaria parasite Plasmodium falciparum exploits antigenic diversity and within-host antigenic variation to evade the host's immune system. of particular importance are the highly polymorphic var genes that encode the family of cell surface antigens PfEMP1 (Plasmodium falciparum Erythrocyte Membrane Protein 1). It has recently been shown that in spite of their extreme diversity, however, these genes fall into distinct groups according to chromosomal location or sequence similarity, and that recombination may be confined within these groups. METHODS: This study presents a mathematical analysis of how recombination hierarchies affect diversity, and, by using simple stochastic simulations, investigates how intra- and inter-genic diversity influence the rate at which individuals acquire clinical immunity. RESULTS: the analysis demonstrates that the partitioning of the var gene repertoire has a limiting effect on the total diversity attainable through recombination and that the limiting effect is strongly influenced by the respective sizes of each of the partitions. Furthermore, by associating expression of one of the groups with severe malaria it is demonstrated how a small number of infections can be sufficient to protect against disease despite a seemingly limitless number of possible non-identical repertoires. CONCLUSION: Recombination hierarchies within the var gene repertoire of P. falciparum have a severe effect on strain diversity and the process of acquiring immunity against clinical malaria. Future studies will show how the existence of these recombining groups can offer an evolutionary advantage in spite of their restriction on diversity.
Abstract.
Author URL.
2007
Recker M, Pybus OG, Nee S, Gupta S (2007). The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types.
Proc Natl Acad Sci U S A,
104(18), 7711-7716.
Abstract:
The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types.
It is commonly believed that influenza epidemics arise through the incremental accumulation of viral mutations, culminating in a novel antigenic type that is able to escape host immunity. Successive epidemic strains therefore become increasingly antigenically distant from a founding strain. Here, we present an alternative explanation where, because of functional constraints on the defining epitopes, the virus population is characterized by a limited set of antigenic types, all of which may be continuously generated by mutation from preexisting strains and other processes. Under these circumstances, influenza outbreaks arise as a consequence of host immune selection in a manner that is independent of the mode and tempo of viral mutation. By contrast with existing paradigms, antigenic distance between epidemic strains does not necessarily accumulate with time in our model, and it is the changing profile of host population immunity that creates the conditions for the emergence of the next influenza strain rather than the mutational capabilities of the virus.
Abstract.
Author URL.
2006
Recker M, Gupta S (2006). Conflicting immune responses can prolong the length of infection in Plasmodium falciparum malaria.
Bull Math Biol,
68(4), 821-835.
Abstract:
Conflicting immune responses can prolong the length of infection in Plasmodium falciparum malaria.
We have recently proposed a new model for antigenic variation in Plasmodium falciparum that relies on a network of partially cross-protective immune responses to orchestrate this complex immune evasion process. In addition to exhibiting prolonged oscillations of single variants that resemble the sequential dominance of immunologically distinct antigenic types, the model implies that a higher efficacy of cross-reactive immunity actually increases the length of infection while reducing severity of disease. Here, we analyse the behaviour of a reduced system under conditions of perfect synchrony between variants to demonstrate that these features of this system can be attributed to the antagonism between cross-reactive and variant-specific responses.
Abstract.
Author URL.
Massey RC, Horsburgh MJ, Lina G, Höök M, Recker M (2006). The evolution and maintenance of virulence in Staphylococcus aureus: a role for host-to-host transmission?.
Nat Rev Microbiol,
4(12), 953-958.
Abstract:
The evolution and maintenance of virulence in Staphylococcus aureus: a role for host-to-host transmission?
Despite progress in our understanding of infectious disease biology and prevention, the conditions that select for the establishment and maintenance of microbial virulence remain enigmatic. To address this aspect of pathogen biology, we focus on two members of the Staphylococcus genus - Staphylococcus aureus and Staphylococcus epidermidis - and consider why S. aureus has evolved to become more virulent than S. epidermidis. Several hypotheses to explain this phenomenon are discussed and a mathematical model is used to argue that a complex transmission pathway is the key factor in explaining the evolution and maintenance of virulence in S. aureus. In the case of S. epidermidis, where skin contact affords easier transmission between hosts, high levels of virulence do not offer an advantage to this pathogen.
Abstract.
Author URL.
2005
Recker M, Al-Bader R, Gupta S (2005). A mathematical model for a new mechanism of phenotypic variation in malaria.
Parasitology,
131(2), 151-159.
Abstract:
A mathematical model for a new mechanism of phenotypic variation in malaria
The Py235 merozoite rhoptry protein of the rodent malaria agent Plasmodium (yoelii) yoeli is encoded by the Py235 multigene family whose members are transcribed during the parasite's asexual life-cycle in a fashion where single schizonts subsequently give rise to sets of merozoites containing distinct Py235 transcripts. Homologues of Py235 are found in other malaria species, and antibodies to both Py235 and P. falciparum homologues inhibit merozoite invasion, suggesting a unique survival strategy involving immune evasion and host adaptation. Using a mathematical approach to model this free-living stage of Plasmodium in interaction with specific antibodies and a heterogeneous red blood cell population, we investigate if, and under what conditions, this mechanism of clonal phenotypic variation can play a role in immune evasion and adaptation to a dynamic erythropoietic environment. © 2005 Cambridge University Press.
Abstract.
Recker M, Al-Bader R, Gupta S (2005). A mathematical model for a new mechanism of phenotypic variation in malaria.
Parasitology,
131(Pt 2), 151-159.
Abstract:
A mathematical model for a new mechanism of phenotypic variation in malaria.
The Py235 merozoite rhoptry protein of the rodent malaria agent Plasmodium (yoelii) yoeli is encoded by the Py235 multigene family whose members are transcribed during the parasite's asexual life-cycle in a fashion where single schizonts subsequently give rise to sets of merozoites containing distinct Py235 transcripts. Homologues of Py235 are found in other malaria species, and antibodies to both Py235 and P. falciparum homologues inhibit merozoite invasion, suggesting a unique survival strategy involving immune evasion and host adaptation. Using a mathematical approach to model this free-living stage of Plasmodium in interaction with specific antibodies and a heterogeneous red blood cell population, we investigate if, and under what conditions, this mechanism of clonal phenotypic variation can play a role in immune evasion and adaptation to a dynamic erythropoietic environment.
Abstract.
Author URL.
Recker M, Gupta S (2005). A model for pathogen population structure with cross-protection depending on the extent of overlap in antigenic variant repertoires.
J Theor Biol,
232(3), 363-373.
Abstract:
A model for pathogen population structure with cross-protection depending on the extent of overlap in antigenic variant repertoires.
The persistence of discrete antigenic types among pathogens with multiple immunogenic loci can be explained by the action of immune-mediated competition. It has previously been shown that pathogen populations will self-organize into non-overlapping subsets of antigenic variants if cross-protection between pathogen types sharing any variants is high. Here, we examine the critical question of whether such strain structure will emerge if the degree of immune-mediated competition is dependent on the number of variants shared between pathogen types, rather than in an all-or-nothing manner. Our analysis uncovers a progression from no strain structure through to discrete stable strain structure through intermediate partially structured states. This suggests that the number of loci or epitope regions required to detect linkage disequilibrium (as a manifestation of stable discrete strain structure) in pathogen populations correlates inversely with the strength of immune selection.
Abstract.
Author URL.
Williams TN, Mwangi TW, Wambua S, Peto TEA, Weatherall DJ, Gupta S, Recker M, Penman BS, Uyoga S, MacHaria A, et al (2005). Negative epistasis between the malaria-protective effects of α<sup>+</sup>-thalassemia and the sickle cell trait.
Nature Genetics,
37(11), 1253-1257.
Abstract:
Negative epistasis between the malaria-protective effects of α+-thalassemia and the sickle cell trait
The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and α+-thalassemia, a condition characterized by reduced production of the normal α-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying α+-thalassemia. Negative epistasis could explain the failure of α+-thalassemia to reach fixation in any population in sub-Saharan Africa. © 2005 Nature Publishing Group.
Abstract.
2004
Recker M, Nee S, Bull PC, Kinyanjui S, Marsh K, Newbold C, Gupta S (2004). Transient cross-reactive immune responses can orchestrate antigenic variation in malaria.
Nature,
429(6991), 555-558.
Abstract:
Transient cross-reactive immune responses can orchestrate antigenic variation in malaria.
The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.
Abstract.
Author URL.
