[Show abstract][Hide abstract] ABSTRACT: Antigens encoded by the var gene family are major virulence factors of the human malaria parasite Plasmodium falciparum, exhibiting enormous intra- and interstrain diversity. Here we use network analysis to show that var architecture and mosaicism are conserved at multiple levels across the Laverania subgenus, based on var-like sequences from eight single-species and three multi-species Plasmodium infections of wild-living or sanctuary African apes. Using select whole-genome amplification, we also find evidence of multi-domain var structure and synteny in Plasmodium gaboni, one of the ape Laverania species most distantly related to P. falciparum, as well as a new class of Duffy-binding-like domains. These findings indicate that the modular genetic architecture and sequence diversity underlying var-mediated host-parasite interactions evolved before the radiation of the Laverania subgenus, long before the emergence of P. falciparum.
[Show abstract][Hide abstract] ABSTRACT: The recent emergence of dengue viruses into new susceptible human populations throughout Asia and the Middle East, driven in part by human travel on both local and global scales, represents a significant global health risk, particularly in areas with changing climatic suitability for the mosquito vector. In Pakistan, dengue has been endemic for decades in the southern port city of Karachi, but large epidemics in the northeast have emerged only since 2011. Pakistan is therefore representative of many countries on the verge of countrywide endemic dengue transmission, where prevention, surveillance, and preparedness are key priorities in previously dengue-free regions. We analyze spatially explicit dengue case data from a large outbreak in Pakistan in 2013 and compare the dynamics of the epidemic to an epidemiological model of dengue virus transmission based on climate and mobility data from ∼40 million mobile phone subscribers. We find that mobile phone-based mobility estimates predict the geographic spread and timing of epidemics in both recently epidemic and emerging locations. We combine transmission suitability maps with estimates of seasonal dengue virus importation to generate fine-scale dynamic risk maps with direct application to dengue containment and epidemic preparedness. dengue | human mobility | Pakistan | mobile phones | epidemiology
Proceedings of the National Academy of Sciences 09/2015; 112(38). DOI:10.1073/pnas.1504964112 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Changing patterns of human aggregation are thought to drive annual and multiannual outbreaks of infectious diseases, but the paucity of data about travel behavior and population flux over time has made this idea difficult to test quantitatively. Current measures of human mobility, especially in low-income settings, are often static, relying on approximate travel times, road networks, or cross-sectional surveys. Mobile phone data provide a unique source of information about human travel, but the power of these data to describe epidemiologically relevant changes in population density remains unclear. Here we quantify seasonal travel patterns using mobile phone data from nearly 15 million anonymous subscribers in Kenya. Using a rich data source of rubella incidence, we show that patterns of population travel (fluxes) inferred from mobile phone data are predictive of disease transmission and improve significantly on standard school term time and weather covariates. Further, combining seasonal and spatial data on travel from mobile phone data allows us to characterize seasonal fluctuations in risk across Kenya and produce dynamic importation risk maps for rubella. Mobile phone data therefore offer a valuable previously unidentified source of data for measuring key drivers of seasonal epidemics.
Proceedings of the National Academy of Sciences 09/2015; 112(35):11114-9. DOI:10.1073/pnas.1423542112 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Simple spatial interaction models of human mobility based on physical laws have been used extensively in the social, biological, and physical sciences, and in the study of the human dynamics underlying the spread of disease. Recent analyses of commuting patterns and travel behavior in high-income countries have led to the suggestion that these models are highly generalizable, and as a result, gravity and radiation models have become standard tools for describing population mobility dynamics for infectious disease epidemiology. Communities in Sub-Saharan Africa may not conform to these models, however; physical accessibility, availability of transport, and cost of travel between locations may be variable and severely constrained compared to high-income settings, informal labor movements rather than regular commuting patterns are often the norm, and the rise of mega-cities across the continent has important implications for travel between rural and urban areas. Here, we first review how infectious disease frameworks incorporate human mobility on different spatial scales and use anonymous mobile phone data from nearly 15 million individuals to analyze the spatiotemporal dynamics of the Kenyan population. We find that gravity and radiation models fail in systematic ways to capture human mobility measured by mobile phones; both severely overestimate the spatial spread of travel and perform poorly in rural areas, but each exhibits different characteristic patterns of failure with respect to routes and volumes of travel. Thus, infectious disease frameworks that rely on spatial interaction models are likely to misrepresent population dynamics important for the spread of disease in many African populations.
[Show abstract][Hide abstract] ABSTRACT: The bacterial pathogen, Streptococcus pneumoniae (the pneumococcus), is a leading cause of life-threatening illness and death worldwide. Available conjugate vaccines target only a small subset (up to 13) of >90 known capsular serotypes of S. pneumoniae and, since their introduction, increases in non-vaccine serotypes have been recorded in several countries: a phenomenon termed Vaccine Induced Serotype Replacement (VISR). Here, using a combination of mathematical modelling and whole genome analysis, we show that targeting particular serotypes through vaccination can also cause their metabolic and virulence-associated components to transfer through recombination to non-vaccine serotypes: a phenomenon we term Vaccine-Induced Metabolic Shift (VIMS). Our results provide a novel explanation for changes observed in the population structure of the pneumococcus following vaccination, and have important implications for strain-targeted vaccination in a range of infectious disease systems.
[Show abstract][Hide abstract] ABSTRACT: Malaria remains one of the leading causes of death worldwide, despite decades of public health efforts. The recent commitment by many endemic countries to eliminate malaria marks a shift away from programs aimed at controlling disease burden towards one that emphasizes reducing transmission of the most virulent human malaria parasite, Plasmodium falciparum. Gametocytes, the only developmental stage of malaria parasites able to infect mosquitoes, have remained understudied, as they occur in low numbers, do not cause disease, and are difficult to detect in vivo by conventional methods. Here, we review the transmission biology of P. falciparum gametocytes, featuring important recent discoveries of genes affecting parasite commitment to gametocyte formation, microvesicles enabling parasites to communicate with each other, and the anatomical site where immature gametocytes develop. We propose potential parasite targets for future intervention and highlight remaining knowledge gaps.
[Show abstract][Hide abstract] ABSTRACT: The duration of infection is fundamental to the epidemiological behaviour of any infectious disease, but remains one of the most poorly understood aspects of malaria. In endemic areas, the malaria parasite Plasmodium falciparum can cause both acute, severe infections and asymptomatic, chronic infections through its interaction with the host immune system. Frequent superinfection and massive parasite genetic diversity make it extremely difficult to accurately measure the distribution of infection lengths, complicating the estimation of basic epidemiological parameters and the prediction of the impact of interventions. Mathematical models have qualitatively reproduced parasite dynamics early during infection, but reproducing long-lived chronic infections remains much more challenging. Here, we construct a model of infection dynamics to examine the consequences of common biological assumptions for the generation of chronicity and the impact of co-infection. We find that although a combination of host and parasite heterogeneities are capable of generating chronic infections, they do so only under restricted parameter choices. Furthermore, under biologically plausible assumptions, co-infection of parasite genotypes can alter the course of infection of both the resident and co-infecting strain in complex non-intuitive ways. We outline the most important puzzles for within-host models of malaria arising from our analysis, and their implications for malaria epidemiology and control.
Journal of The Royal Society Interface 03/2015; 12(104). DOI:10.1098/rsif.2014.1379 · 3.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Poor physical access to health facilities has been identified as an important contributor to reduced uptake of preventive health services and is likely to be most critical in low-income settings. However, the relation among physical access, travel behavior, and the uptake of healthcare is difficult to quantify.
Using anonymized mobile phone data from 2008 to 2009, we analyze individual and spatially aggregated travel patterns of 14,816,521 subscribers across Kenya and compare these measures to (1) estimated travel times to health facilities and (2) data on the uptake of 2 preventive healthcare interventions in an area of western Kenya: childhood immunizations and antenatal care.
We document that long travel times to health facilities are strongly correlated with increased mobility in geographically isolated areas. Furthermore, we found that in areas with equal physical access to healthcare, mobile phone-derived measures of mobility predict which regions are lacking preventive care.
Routinely collected mobile phone data provide a simple and low-cost approach to mapping the uptake of preventive healthcare in low-income settings.
[Show abstract][Hide abstract] ABSTRACT: As the intensity of malaria transmission has declined, Plasmodium falciparum parasite populations have displayed decreased clonal diversity resulting from the emergence of many parasites with common
genetic signatures (CGS). We have monitored such CGS parasite clusters from 2006 to 2013 in Thiès, Senegal, using the molecular
barcode. The first, and one of the largest observed clusters of CGS parasites, was present in 24% of clinical isolates in
2008, declined to 3.4% of clinical isolates in 2009, and then disappeared. To begin to explore the relationship between the
immune responses of the population and the emergence and decline of specific parasite genotypes, we have determined whether
antibodies to CGS parasites correlate with their prevalence. We measured (i) antibodies capable of inhibiting parasite growth
in culture and (ii) antibodies recognizing the surfaces of infected erythrocytes (RBCs). IgG obtained from volunteers in 2009
showed increased reactivity to the surfaces of CGS-parasitized erythrocytes over IgG from 2008. Since P. falciparum EMP-1 (PfEMP-1) is a major variant surface antigen, we used var Ups quantitative reverse transcription-PCR (qRT-PCR) and sequencing with degenerate DBL1α domain primers to characterize
the var genes expressed by CGS parasites after short-term in vitro culture. CGS parasites show upregulation of UpsA var genes and 2-cysteine-containing PfEMP-1 molecules and express the same dominant var transcript. Our work indicates that the CGS parasites in this cluster express similar var genes, more than would be expected by chance in the population, and that there is year-to-year variation in immune recognition
of surface antigens on CGS parasite-infected erythrocytes. This study lays the groundwork for detailed investigations of the
mechanisms driving the expansion or contraction of specific parasite clones in the population.
Infection and Immunity 11/2014; 83(1). DOI:10.1128/IAI.01979-14 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pathogen evolution is influenced strongly by the host immune response. Previous studies of the effects of herd immunity on the population structure of directly transmitted, short-lived pathogens have primarily focused on the impact of competition for hosts. In contrast, for long-lived infections like HIV, theoretical work has focused on the mechanisms promoting antigenic variation within the host. In reality, successful transmission requires that pathogens balance both within- and between-host immune selection. The Opa adhesins in the bacterial Neisseria genus provide a unique system to study the evolution of the same antigens across two major pathogens: while N. meningitidis is an airborne, respiratory pathogen colonising the nasopharynx relatively transiently, N. gonorrhoeae can cause sexually transmitted, long-lived infections. We use a simple mathematical model and genomic data to show that trade-offs between immune selection pressures within- and between-hosts can explain the contrasting Opa repertoires observed in meningococci and gonococci.
[Show abstract][Hide abstract] ABSTRACT: The asexual forms of the malaria parasite Plasmodium falciparum are adapted for chronic persistence in human red blood cells, continuously evading host immunity using epigenetically regulated antigenic variation of virulence-associated genes. Parasite survival on a population level also requires differentiation into sexual forms, an obligatory step for further human transmission. We reveal that the essential nuclear gene, P. falciparum histone deacetylase 2 (PfHda2), is a global silencer of virulence gene expression and controls the frequency of switching from the asexual cycle to sexual development. PfHda2 depletion leads to dysregulated expression of both virulence-associated var genes and PfAP2-g, a transcription factor controlling sexual conversion, and is accompanied by increases in gametocytogenesis. Mathematical modeling further indicates that PfHda2 has likely evolved to optimize the parasite's infectious period by achieving low frequencies of virulence gene expression switching and sexual conversion. This common regulation of cellular transcriptional programs mechanistically links parasite transmissibility and virulence.
[Show abstract][Hide abstract] ABSTRACT: Human travel impacts the spread of infectious diseases across spatial and temporal scales, with broad implications for the biological and social sciences. Individual data on travel patterns have been difficult to obtain, particularly in low-income countries. Travel survey data provide detailed demographic information, but sample sizes are often small and travel histories are hard to validate. Mobile phone records can provide vast quantities of spatio-temporal travel data but vary in spatial resolution and explicitly do not include individual information in order to protect the privacy of subscribers. Here we compare and contrast both sources of data over the same time period in a rural area of Kenya. Although both data sets are able to quantify broad travel patterns and distinguish regional differences in travel, each provides different insights that can be combined to form a more detailed picture of travel in low-income settings to understand the spread of infectious diseases.
[Show abstract][Hide abstract] ABSTRACT: Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world. Efforts to control these diseases have been underpinned by a theoretical framework developed for malaria by Ross and Macdonald, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle. That framework, especially Macdonald's formula for R0 and its entomological derivative, vectorial capacity, are now used to study dynamics and design interventions for many mosquito-borne diseases. A systematic review of 388 models published between 1970 and 2010 found that the vast majority adopted the Ross-Macdonald assumption of homogeneous transmission in a well-mixed population. Studies comparing models and data question these assumptions and point to the capacity to model heterogeneous, focal transmission as the most important but relatively unexplored component in current theory. Fine-scale heterogeneity causes transmission dynamics to be nonlinear, and poses problems for modeling, epidemiology and measurement. Novel mathematical approaches show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold. Emerging theory focuses attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control.
Transactions of the Royal Society of Tropical Medicine and Hygiene 04/2014; 108(4):185-197. DOI:10.1093/trstmh/tru026 · 1.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pathogen-mediated selection is commonly invoked as an explanation for the exceptional polymorphism of the HLA gene cluster, but its role in generating and maintaining linkage disequilibrium between HLA loci is unclear. Here we show that pathogen-mediated selection can promote nonrandom associations between HLA loci. These associations may be distinguished from linkage disequilibrium generated by other population genetic processes by virtue of being nonoverlapping as well as nonrandom. Within our framework, immune selection forces the pathogen population to exist as a set of antigenically discrete strains; this then drives nonoverlapping associations between the HLA loci through which recognition of these antigens is mediated. We demonstrate that this signature of pathogen-driven selection can be observed in existing data, and propose that analyses of HLA population structure can be combined with laboratory studies to help us uncover the functional relationships between HLA alleles. In a wider coevolutionary context, our framework also shows that the inclusion of memory immunity can lead to robust cyclical dynamics across a range of host-pathogen systems.
Proceedings of the National Academy of Sciences 11/2013; 110(48). DOI:10.1073/pnas.1304218110 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The var genes of the human malaria parasite Plasmodium falciparum present a challenge to population geneticists due to their extreme diversity, which is generated by high rates of recombination. These genes encode a primary antigen protein called PfEMP1, which is expressed on the surface of infected red blood cells and elicits protective immune responses. Var gene sequences are characterized by pronounced mosaicism, precluding the use of traditional phylogenetic tools that require bifurcating tree-like evolutionary relationships. We present a new method that identifies highly variable regions (HVRs), and then maps each HVR to a complex network in which each sequence is a node and two nodes are linked if they share an exact match of significant length. Here, networks of var genes that recombine freely are expected to have a uniformly random structure, but constraints on recombination will produce network communities that we identify using a stochastic block model. We validate this method on synthetic data, showing that it correctly recovers populations of constrained recombination, before applying it to the Duffy Binding Like-α (DBLα) domain of var genes. We find nine HVRs whose network communities map in distinctive ways to known DBLα classifications and clinical phenotypes. We show that the recombinational constraints of some HVRs are correlated, while others are independent. These findings suggest that this micromodular structuring facilitates independent evolutionary trajectories of neighboring mosaic regions, allowing the parasite to retain protein function while generating enormous sequence diversity. Our approach therefore offers a rigorous method for analyzing evolutionary constraints in var genes, and is also flexible enough to be easily applied more generally to any highly recombinant sequences.
[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 07/2013; 8(7):e70467. DOI:10.1371/journal.pone.0070467 · 3.23 Impact Factor