A Network Approach to Analyzing Highly Recombinant Malaria Parasite Genes

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

Inferring malaria parasite population structure from serological networks

The malaria parasite Plasmodium falciparum is characterized by high levels of genetic diversity at antigenic loci involved in virulence and immune evasion. Knowledge of the population structure and dynamics of these genes is important for designing control programmes and understanding the acquisition of immunity to malaria; however, high rates of homologous and non-homologous recombination as well as complex patterns of expression within hosts have hindered attempts to elucidate these structures experimentally. Here, we analyse serological data from Kenya using a novel network technique to deconstruct the relationships between patients' immune responses to different parasite isolates. We show that particular population structures and expression patterns produce distinctive signatures within serological networks of parasite recognition, which can be used to discriminate between competing hypotheses regarding the organization of these genes. Our analysis suggests that different levels of immune selection occur within different groups of the same multigene family leading to mixed population structures

Mathematical Models for a New Era of Malaria Eradication

Maciej Boni and colleagues discuss a new model exploring how a switch in antimalarial drug use to artemisinin-based combination therapies will affect malaria prevalence and incidence in endemic regions

Heterogeneous Mobile Phone Ownership and Usage Patterns in Kenya

The rapid adoption of mobile phone technologies in Africa is offering exciting opportunities for engaging with high-risk populations through mHealth programs, and the vast volumes of behavioral data being generated as people use their phones provide valuable data about human behavioral dynamics in these regions. Taking advantage of these opportunities requires an understanding of the penetration of mobile phones and phone usage patterns across the continent, but very little is known about the social and geographical heterogeneities in mobile phone ownership among African populations. Here, we analyze a survey of mobile phone ownership and usage across Kenya in 2009 and show that distinct regional, gender-related, and socioeconomic variations exist, with particularly low ownership among rural communities and poor people. We also examine patterns of phone sharing and highlight the contrasting relationships between ownership and sharing in different parts of the country. This heterogeneous penetration of mobile phones has important implications for the use of mobile technologies as a source of population data and as a public health tool in sub-Saharan Africa

Quantifying travel behavior for infectious disease research: a comparison of data from surveys and mobile phones.

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

Multilocus haplotypes reveal variable levels of diversity and population structure of Plasmodium falciparum in Papua New Guinea, a region of intense perennial transmission

<p>Abstract</p> <p>Background</p> <p>The South West Pacific nation of Papua New Guinea has intense year round transmission of <it>Plasmodium falciparum </it>on the coast and in the low-lying inland areas. Local heterogeneity in the epidemiology of malaria suggests that parasites from multiple locations will need to be surveyed to define the population biology of <it>P. falciparum </it>in the region. This study describes the population genetics of <it>P. falciparum </it>in thirteen villages spread over four distinct catchment areas of Papua New Guinea.</p> <p>Methods</p> <p>Ten microsatellite loci were genotyped in 318 <it>P. falciparum </it>isolates from the parasite populations of two inland catchment areas, namely Wosera (number of villages (n) = 7) and Utu (n = 1) and; and two coastal catchments, Malala (n = 3) and Mugil (n = 3). Analysis of the resultant multilocus haplotypes was done at different spatial scales (2-336 km) to define the genetic diversity (allelic richness and expected heterozygosity), linkage disequilibrium and population structure throughout the study area.</p> <p>Results</p> <p>Although genetic diversity was high in all parasite populations, it was also variable with a lower allelic richness and expected heterozygosity for inland populations compared to those from the more accessible coast. This variability was not correlated with two proxy measures of transmission intensity, the infection prevalence and the proportion multiple infections. Random associations among the microsatellite loci were observed in all four catchments showing that a substantial degree of out-crossing occurs in the region. Moderate to very high levels of population structure were found but the amount of genetic differentiation (<it>F_ST</it>) did not correlate with geographic distance suggesting that parasite populations are fragmented. Population structure was also identified between villages within the Malala area, with the haplotypes of one parasite population clustering with the neighbouring catchment of Mugil.</p> <p>Conclusion</p> <p>The observed population genetics of <it>P. falciparum </it>in this region is likely to be a consequence of the high transmission intensity combined with the isolation of human and vector populations, especially those located inland and migration of parasites via human movement into coastal populations. The variable genetic diversity and population structure of <it>P. falciparum </it>has important implications for malaria control strategies and warrants further fine scale sampling throughout Papua New Guinea.</p

Introduction of rubella-containing-vaccine to Madagascar: implications for roll-out and local elimination

Few countries in Africa currently include rubella-containing vaccination (RCV) in their immunization schedule. The Global Alliance for Vaccines Initiative (GAVI) recently opened a funding window that has motivated more widespread roll-out of RCV. As countries plan RCV introductions, an understanding of the existing burden, spatial patterns of vaccine coverage, and the impact of patterns of local extinction and reintroduction for rubella will be critical to developing effective programmes. As one of the first countries proposing RCV introduction in part with GAVI funding, Madagascar provides a powerful and timely case study. We analyse serological data from measles surveillance systems to characterize the epidemiology of rubella in Madagascar. Combining these results with data on measles vaccination delivery, we develop an age-structured model to simulate rubella vaccination scenarios and evaluate the dynamics of rubella and the burden of congenital rubella syndrome (CRS) across Madagascar. We additionally evaluate the drivers of spatial heterogeneity in age of infection to identify focal locations where vaccine surveillance should be strengthened and where challenges to successful vaccination introduction are expected. Our analyses indicate that characteristics of rubella in Madagascar are in line with global observations, with an average age of infection near 7 years, and an impact of frequent local extinction with reintroductions causing localized epidemics. Modelling results indicate that introduction of RCV into the routine programme alone may initially decrease rubella incidence but then result in cumulative increases in the burden of CRS in some regions (and transient increases in this burden in many regions). Deployment of RCV with regular supplementary campaigns will mitigate these outcomes. Results suggest that introduction of RCV offers a potential for elimination of rubella in Madagascar, but also emphasize both that targeted vaccination is likely to be a lynchpin of this success, and the public health vigilance that this introduction will require

Long-term evolution of antigen repertoires among carried meningococci

Most studies of bacterial pathogen populations have been based on isolates collected from individuals with disease, or their contacts, over short time periods. For commensal organisms that occasionally cause disease, such as Neisseria meningitidis, however, the analysis of isolates from long-term asymptomatic carriage is necessary to elucidate their evolution and population structure. Here, we use mathematical models to analyse the structuring and dynamics of three vaccine-candidate antigens among carried meningococcal isolates collected over nearly 30 years in the Czech Republic. The data indicate that stable combinations of antigenic alleles were maintained over this time period despite evidence for high rates of recombination, consistent with theoretical models in which strong immune selection can maintain non-overlapping combinations of antigenic determinants in the presence of recombination. We contrast this antigenic structure with the overlapping but relatively stable combinations of the housekeeping genes observed among the same isolates, and use a novel network approach to visualize these relationships

Quantifying travel behavior for infectious disease research: a comparison of data from surveys and mobile phones

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

A Plasmodium falciparum Histone Deacetylase Regulates Antigenic Variation and Gametocyte Conversion

SummaryThe 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