Elucidating relationships between P.falciparum prevalence and measures of genetic diversity with a combined genetic-epidemiological model of malaria

There is an abundance of malaria genetic data being collected from the field, yet using these data to understand the drivers of regional epidemiology remains a challenge. A key issue is the lack of models that relate parasite genetic diversity to epidemiological parameters. Classical models in population genetics characterize changes in genetic diversity in relation to demographic parameters, but fail to account for the unique features of the malaria life cycle. In contrast, epidemiological models, such as the Ross-Macdonald model, capture malaria transmission dynamics but do not consider genetics. Here, we have developed an integrated model encompassing both parasite evolution and regional epidemiology. We achieve this by combining the Ross-Macdonald model with an intra-host continuous-time Moran model, thus explicitly representing the evolution of individual parasite genomes in a traditional epidemiological framework. Implemented as a stochastic simulation, we use the model to explore relationships between measures of parasite genetic diversity and parasite prevalence, a widely-used metric of transmission intensity. First, we explore how varying parasite prevalence influences genetic diversity at equilibrium. We find that multiple genetic diversity statistics are correlated with prevalence, but the strength of the relationships depends on whether variation in prevalence is driven by host- or vector-related factors. Next, we assess the responsiveness of a variety of statistics to malaria control interventions, finding that those related to mixed infections respond quickly (∼months) whereas other statistics, such as nucleotide diversity, may take decades to respond. These findings provide insights into the opportunities and challenges associated with using genetic data to monitor malaria epidemiology.     

Ruminating on complexity: macroparasites of wildlife and livestock

Recent advances in ecology have improved our understanding of the role of parasites in the dynamics of wildlife populations. However, conditions that prevail in many wildlife systems, such as host movement, contact with livestock, and heterogeneity in the environment of the parasite outside of the host, have largely been ignored in existing models of macroparasite transmission. We need to refine these models if we are to stand a chance of developing effective parasite control strategies. New quantitative approaches enable us to address key complexities and make better use of scarce data, and these should enhance our efforts to understand and control emerging problems of interspecific parasite transmission.     

Evolution of host life-history traits in a spatially structured host-parasite system

Most models for the evolution of host defense against parasites assume that host populations are not spatially structured. Yet local interactions and limited dispersal can strongly affect the evolutionary outcome, because they significantly alter epidemiological feedbacks and the spatial genetic structuring of the host and pathogen populations. We provide a general framework to study the evolution of a number of host life-history traits in a spatially structured host population infected by a horizontally transmitted parasite. Our analysis teases apart the selective pressures on hosts and helps disentangle the direct fitness effect of mutations and their indirect effects via the influence of spatial structure on the genetic, demographic, and epidemiological structure of the host population. We then illustrate the evolutionary consequences of spatial structure by focusing on the evolution of two host defense strategies against parasitism: suicide upon infection and reduced transmission. Because they bring no direct fitness benefit, these strategies are counterselected or selectively neutral in a nonspatial setting, but we show that they can be selected for in a spatially structured environment. Our study thus sheds light on the evolution of altruistic defense mechanisms that have been observed in various biological systems.     

Optimal infection strategies: should macroparasites hedge their bets?

Despite considerable research into the mechanisms that lead to the persistence of parasites, the huge diversity of macroparasite transmission strategies observed both within and among species has yet to be explained. This may be because questions of parasite persistence are typically addressed at the population level, even though observed transmission rates are determined by infection events at the level of the individual parasite. To help overcome this disparity, a simple model is developed to explore the optimal infection strategy for a macroparasite under a range of selection pressures. The model calculates the fitness of the parasite by considering explicitly the probability of the individual infective stages surviving and infecting. The optimal strategy is highly sensitive to the rate of host availability and, considering the parasite's fitness, it is often preferable to have sub-maximal infectivity to maximise survival during periods of host absence. An important finding is that when parasites are faced with unpredictable conditions such as the time of host availability, the optimum strategy may be to produce offspring that differ in their infection strategies. By spreading the risk in this way, known as bet hedging, parasites can increase the chances that at least some of their offspring will infect successfully. This potential for variation in infection strategies has not been considered explicitly before and may have wide reaching implications for current epidemiology theory.     

La Trypanosomose Humaine Africaine dans l’espace ivoiro-burkinabé : optimisation des stratégies de surveillance épidémiologique

The objective of this paper was to describe recent data from Burkina Faso and Côte d’Ivoire on Human African Trypanosomosis medical monitoring in order to (i) update the disease situation in these two countries that have been sharing important migratory, economic and epidemiological links for more than a century and (ii) to define the future strategic plans to achieve the goal of a sustainable control/elimination process. Results of active and passive surveillance indicate that all sleeping sickness patients diagnosed these last years in Burkina Faso were imported cases from Côte d’Ivoire. Nevertheless the re-introduction of the parasite is effective and the risk of a resumption of transmission exists. In Côte d’Ivoire, few cases are still diagnosed in several historical foci and the fear exists that the disease could reemerge in these foci or spread to other areas. In order to achieve a sustainable elimination of sleeping sickness in these two countries, control entities have to adapt their strategy to the different epidemiological contexts. At the exception of specific cases, the current disease prevalence no longer justifies the use of expensive medical surveys by exhaustive screening of the population. New disease control strategies, based on the exchange of epidemiological information between the two countries and integrated to the regular national health systems are required to target priority intervention areas. Follow-up in time of both treated patients and serological suspects that are potential asymptomatic carriers of parasite is also important. In parallel, researchers need to better characterize the respective roles of the human and animal reservoir in the maintenance of transmission and evaluate the different control strategies taken by National Control Programs in term of cost/effectiveness to help optimize them.     

The virulence–transmission relationship in an obligate killer holds under diverse epidemiological and ecological conditions,but where is the tradeoff?

Parasite virulence is a leading theme in evolutionary biology. Modeling the course of virulence evolution holds the promise of providing practical insights into the management of infectious diseases and the implementation of vaccination strategies. A key element of virulence modeling is a tradeoff between parasite transmission rate and host lifespan. This assumption is crucial for predicting the level of optimal virulence. Here, I test this assumption using the water flea Daphnia magna and its castrating and obligate‐killing bacterium Pasteuria ramosa. I found that the virulence–transmission relationship holds under diverse epidemiological and ecological conditions. In particular, parasite genotype, absolute and relative parasite dose, and within‐host competition in multiple infections did not significantly affect the observed trend. Interestingly, the relationship between virulence and parasite transmission in this system is best explained by a model that includes a cubic term. Under this relationship, parasite transmission initially peaks and saturates at an intermediate level of virulence, but then it further increases as virulence decreases, surpassing the previous peak. My findings also highlight the problem of using parasite‐induced host mortality as a “one‐size‐fits‐all” measure of virulence for horizontally transmitted parasites, without considering the onset and duration of parasite transmission as well as other equally virulent effects of parasites (e.g., host castration). Therefore, mathematical models may be required to predict whether these particular characteristics of horizontally transmitted parasites can direct virulence evolution into directions not envisaged by existing models.     

The effects of social structure and sex-biased transmission on macroparasite infection

Mathematical models of disease dynamics tend to assume that individuals within a population mix at random and so transmission is random, and yet, in reality social structure creates heterogeneous contact patterns. We investigated the effect of heterogeneity in host contact patterns on potential macroparasite transmission by first quantifying the level of assortativity in a socially structured wild rodent population (Apodemus flavicollis) with respect to the directly-transmitted macroparasitic helminth, Heligmosomoides polygyrus. We found the population to be disassortatively mixed (i.e. male mice mixing with female mice more often than same sex mixing) at a constant level over time. The macroparasite H. polygyrus has previously been shown to exhibit male-biased transmission so we used a Susceptible-Infected (SI) mathematical model to simulate the effect of increasing strengths of male-biased transmission on the prevalence of the macroparasite using empirically-derived transmission networks. When transmission was equal between the sexes the model predicted macroparasite prevalence to be 73% and infection was male biased (82% of infection in the male mice). With a male-bias in transmission ten times that of the females, the expected macroparasite prevalence was 50% and was equally prevalent in both sexes, results that both most closely resembled empirical dynamics. As such, disassortative mixing alone did not produce macroparasite dynamics analogous to those from empirical observations; a strong male-bias in transmission was also required. We discuss the relevance of our results in the context of network models for transmission dynamics and control.     

Bottom–up regulation of parasite population densities in freshwater ecosystems

Theory predicts the bottom–up coupling of resource and consumer densities, and epidemiological models make the same prediction for host–parasite interactions. Empirical evidence that spatial variation in local host density drives parasite population density remains scarce, however. We test the coupling of consumer (parasite) and resource (host) populations using data from 310 populations of metazoan parasites infecting invertebrates and fish in New Zealand lakes, spanning a range of transmission modes. Both parasite density (no. parasites per m²) and intensity of infection (no. parasites per infected hosts) were quantified for each parasite population, and related to host density, spatial variability in host density and transmission mode (egg ingestion, contact transmission or trophic transmission). The results show that dense and temporally stable host populations are exploited by denser and more stable parasite populations. For parasites with multi‐host cycles, density of the ‘source’ host did not matter: only density of the current host affected parasite density at a given life stage. For contact‐transmitted parasites, intensity of infection decreased with increasing host density. Our results support the strong bottom–up coupling of consumer and resource densities, but also suggest that intraspecific competition among parasites may be weaker when hosts are abundant: high host density promotes greater parasite population density, but also reduces the number of conspecific parasites per individual host.     

Identifying Malaria Transmission Foci for Elimination Using Human Mobility Data

Humans move frequently and tend to carry parasites among areas with endemic malaria and into areas where local transmission is unsustainable. Human-mediated parasite mobility can thus sustain parasite populations in areas where they would otherwise be absent. Data describing human mobility and malaria epidemiology can help classify landscapes into parasite demographic sources and sinks, ecological concepts that have parallels in malaria control discussions of transmission foci. By linking transmission to parasite flow, it is possible to stratify landscapes for malaria control and elimination, as sources are disproportionately important to the regional persistence of malaria parasites. Here, we identify putative malaria sources and sinks for pre-elimination Namibia using malaria parasite rate (PR) maps and call data records from mobile phones, using a steady-state analysis of a malaria transmission model to infer where infections most likely occurred. We also examined how the landscape of transmission and burden changed from the pre-elimination setting by comparing the location and extent of predicted pre-elimination transmission foci with modeled incidence for 2009. This comparison suggests that while transmission was spatially focal pre-elimination, the spatial distribution of cases changed as burden declined. The changing spatial distribution of burden could be due to importation, with cases focused around importation hotspots, or due to heterogeneous application of elimination effort. While this framework is an important step towards understanding progressive changes in malaria distribution and the role of subnational transmission dynamics in a policy-relevant way, future work should account for international parasite movement, utilize real time surveillance data, and relax the steady state assumption required by the presented model.     

Sex, subdivision, and domestic dispersal of Trypanosoma cruzi lineage I in southern Ecuador

Background

Molecular epidemiology at the community level has an important guiding role in zoonotic disease control programmes where genetic markers are suitably variable to unravel the dynamics of local transmission. We evaluated the molecular diversity of Trypanosoma cruzi, the etiological agent of Chagas disease, in southern Ecuador (Loja Province). This kinetoplastid parasite has traditionally been a paradigm for clonal population structure in pathogenic organisms. However, the presence of naturally occurring hybrids, mitochondrial introgression, and evidence of genetic exchange in the laboratory question this dogma.

Methodology/Principal Findings

Eighty-one parasite isolates from domiciliary, peridomiciliary, and sylvatic triatomines and mammals were genotyped across 10 variable microsatellite loci. Two discrete parasite populations were defined: one predominantly composed of isolates from domestic and peridomestic foci, and another predominantly composed of isolates from sylvatic foci. Spatial genetic variation was absent from the former, suggesting rapid parasite dispersal across our study area. Furthermore, linkage equilibrium between loci, Hardy-Weinberg allele frequencies at individual loci, and a lack of repeated genotypes are indicative of frequent genetic exchange among individuals in the domestic/peridomestic population.

Conclusions/Significance

These data represent novel population-level evidence of an extant capacity for sex among natural cycles of T. cruzi transmission. As such they have dramatic implications for our understanding of the fundamental genetics of this parasite. Our data also elucidate local disease transmission, whereby passive anthropogenic domestic mammal and triatomine dispersal across our study area is likely to account for the rapid domestic/peridomestic spread of the parasite. Finally we discuss how this, and the observed subdivision between sympatric sylvatic and domestic/peridomestic foci, can inform efforts at Chagas disease control in Ecuador.     

Genetic diversity and population structuring of Schistosoma mansoni in a Brazilian village

The digenean trematode Schistosoma mansoni is responsible for chronic schistosomiasis worldwide, and in Brazil alone an estimated 35 million people are at risk. To evaluate epidemiological patterns among human definitive hosts, we assessed genetic diversity and population subdivision of S. mansoni infrapopulations in human hosts from the highly endemic village of Virgem das Graças in the state of Minas Gerais, Brazil. We believe this is the largest such survey to date. Genetic diversity of parasites, measured over eight polymorphic microsatellite loci, was relatively high and standard measures of inbreeding indicated that the population was panmictic. Furthermore, there was no significant isolation-by-distance of parasite infrapopulations, and measures of population subdivision indicated significant but low to moderate levels of population differentiation. We conclude that patients within this village sample from a broad range of schistosome genetic diversity and effectively act as “genetic mixing bowls” for the parasites. These results contrast with those previously observed in the Brazilian village of Melqu?´ades and thus provide the opportunity for comparisons of environmental and epidemiological differences that are likely to influence host–parasite coevolution and parasite transmission.     

Host and parasite life history interplay to yield divergent population genetic structures in two ectoparasites living on the same bat species

Host–parasite interactions are ubiquitous in nature. However, how parasite population genetic structure is shaped by the interaction between host and parasite life history remains understudied. Studies comparing multiple parasites infecting a single host can be used to investigate how different parasite life history traits interplay with host behaviour and life history. In this study, we used 10 newly developed microsatellite loci to investigate the genetic structure of a parasitic bat fly (Basilia nana). Its host, the Bechstein's bat (Myotis bechsteinii), has a social system and roosting behaviour that restrict opportunities for parasite transmission. We compared fly genetic structure to that of the host and another parasite, the wing‐mite, Spinturnix bechsteini. We found little spatial or temporal genetic structure in B. nana, suggesting a large, stable population with frequent genetic exchange between fly populations from different bat colonies. This contrasts sharply with the genetic structure of the wing‐mite, which is highly substructured between the same bat colonies as well as temporally unstable. Our results suggest that although host and parasite life history interact to yield similar transmission patterns in both parasite species, the level of gene flow and eventual spatiotemporal genetic stability is differentially affected. This can be explained by the differences in generation time and winter survival between the flies and wing‐mites. Our study thus exemplifies that the population genetic structure of parasites on a single host can vary strongly as a result of how their individual life history characteristics interact with host behaviour and life history traits.     

Effective sizes of macroparasite populations: a conceptual model

Effective population size (N(e)) is a crucial parameter in evolutionary biology because it controls genetic drift and the response to selection. Thus, N(e) influences evolutionary processes in parasites, such as speciation, host-race formation, local host adaptation and the evolution of drug resistance. However, N(e) is a parameter that is ignored almost completely in parasitology. Our goal is to provide a conceptual framework that facilitates future studies of the N(e) of macroparasites. The key feature of macroparasite populations is that breeders are subdivided into infrapopulations. We use a model of subdivided breeders to show how some basic demographic factors that control N(e) in all species could be estimated for macroparasites. An important conclusion is that several features of parasite life cycles probably function in concert to reduce N(e) below that expected in a single free-living population of equivalent census size.     

Regional epidemiologic characteristics of combined foci of tick-borne encephalitis, endemic rickettsioses and leptospirosis in Western Siberia

The authors carried out complex study of combined foci of infections with natural foci in Western Siberia and their reflection in human pathology. The results of serological examination of 5917 persons and of 1743 of farm animals in respect to tick-borne encephalitis, Asian tick-borne rickettsiosis, Q-rickettsiosis, and leptospiroses are analysed. Affection of the population with all the four infections in all the landscape zones under study was shown; the intensity of this affection with different infections differed. Combined natural foci of the mentioned infections were found to be widespread; epidemiological significance of such combination was unequal in different ladscapes, this depending on the ladscape characteristics of the natural foci of infections under study and of different ways of transmission of their causative agents.     

Population structures and the role of genetic exchange in the zoonotic pathogen Cryptosporidium parvum

Apicomplexan protozoan parasites include some of the most globally important human and animal pathogens, all of which have obligatory sexual cycles in their definitive hosts. Despite their importance and the relevance of understanding the population genetic structure and role of genetic exchange in generating diversity, population genetic analysis has largely been restricted to Plasmodium spp. and Toxoplasma gondii. These species show a considerable diversity of population structure suggesting different strategies for transmission and survival in mammalian hosts. We have undertaken a population genetic analysis of a further apicomplexan species (Cryptosporidium parvum) to extend our understanding of the diversity of genetic structures and test whether it has a clonal population structure. Nothing is known about the population structure of this parasite. We have analyzed 180 parasite isolates from both humans and cattle derived from a single discrete geographical area, using three minisatellite and four microsatellite markers that define 38 multilocus genotypes. Analysis of linkage disequilibria between pairs of loci combined with measures of genetic distance and similarity provides evidence that the sample comprises four genetically isolated populations. One group of human isolates consists primarily of two closely related multilocus genotypes (clonal), while the major subtypes of a second group, common to both humans and animals, show a panmictic population structure. The data provide an important step in understanding the role of genetic exchange in these parasites, which is an essential prerequisite for determining the value of multilocus genotyping for the analysis of sources of human infection as well as future molecular epidemiological studies.     

Spatial and genetic structure of directly-transmitted parasites reflects the distribution of their specific amphibian hosts

Parasite distributions depend on the local environment in which host infection occurs, and the surrounding landscape over which hosts move and transport their parasites. Although host and landscape effects on parasite prevalence and spatial distribution are difficult to observe directly, estimation of such relationships is necessary for understanding the spread of infections and parasite–habitat associations. Although parasite distributions are necessarily nested within host distributions, direct environmental influences on local infection or parasite effects on host dispersal could lead to distinct landscape or habitat relationships relative to their hosts. Our aim was to determine parasite spatial structure across a contiguous prairie by statistical modeling of parasite–landscape relationships combined with analysis of population genetic structure. We sampled northern leopard frogs (Lithobates pipiens) and wood frogs (L. sylvaticus) for host-specific lung nematodes (Rhabdias ranae and R. bakeri; respectively) across the Sheyenne National Grassland in southeastern North Dakota and developed primers for 13 microsatellite loci for Rhabdias. The two Rhabdias species exhibited different correlations with landscape characteristics that conformed with that of their hosts, indicating transmission is driven by host ecology, probably density, and not directly by the environment. There was evidence for localized, patchy spatial genetic structure, but no broader-scale geographic patterns, indicating no barriers to host and parasite dispersal. Nematodes cohabitating in an individual frog were most genetically similar. Worms within the same wetland were also genetically similar, indicating localized transmission and resulting wetland-scale patchiness are not completely obscured by broad-scale host–parasite dispersal. Beyond individual wetlands, we found no evidence of genetic isolation-by-distance or patchiness at the landscape-scale.     

Worms and germs: the population dynamic consequences of microparasite-macroparasite co-infection

Hosts are typically simultaneously co-infected by a variety of microparasites (e.g. viruses and bacteria) and macroparasites (e.g. parasitic helminths). However, the population dynamical consequences of such co-infections and the implications for the effectiveness of imposed control programmes have yet to be fully realised. Mathematical models may provide an important framework for exploring such issues and have proved invaluable in helping to understand the factors affecting the epidemiology of single parasitic infections. Here the first population dynamic model of microparasite-macroparasite co-infection is presented and used to explore how co-infection alters the predictions of the existing single-species models. It is shown that incorporating an additional parasite species into existing models can greatly stabilise them, due to the combined density-dependent impacts on the host population, but co-infection can also restrict the region of parameter space where each species could persist alone. Overall it is concluded that the dynamic feedback between host, microparasite and macroparasite means that it is difficult to appreciate the factors affecting parasite persistence and predict the effectiveness of control by just studying one component in isolation.     

Interspecific competition among macroparasites in a density-dependent host population

 We analyze the dynamics of a community of macroparasite species that share the same host. Our work extends an earlier framework for a host species that would grow exponentially in the absence of parasitism, to one where an uninfected host population is regulated by factors other than parasites. The model consists of one differential equation for each parasite species and a single density-dependent nonlinear equation for the host. We assume that each parasite species has a negative binomial distribution within the host and there is zero covariance between the species (exploitation competition). New threshold conditions on model parameters for the coexistence and competitive exclusion of parasite species are derived via invadibility and stability analysis of corresponding equilibria. The main finding is that the community of parasite species coexisting at the stable equilibrium is obtained by ranking the species according t! o th e minimum host density H ^* above which a parasite species can grow when rare: the lower H ^* , the higher the competitive ability. We also show that ranking according to the basic reproduction number Q ₀ does not in general coincide with ranking according to H ^* . The second result is that the type of interaction between host and parasites is crucial in determining the competitive success of a parasite species, because frequency-dependent transmission of free-living stages enhances the invading ability of a parasite species while density-dependent transmission makes a parasite very sensitive to other competing species. Finally, we show that density dependence in the host population entails a simplification of the portrait of possible outcomes with respect to previous studies, because all the cases resulting in the exponential growth of host and parasite populations are eliminated.. Received: 24 June 1996 / Revised version: 28 April 1998     

Drivers of Echinococcus multilocularis Transmission in China: Small Mammal Diversity,Landscape or Climate?

Background

Human alveolar echinococcocosis (AE) is a highly pathogenic zoonotic disease caused by the larval stage of the cestode E. multilocularis. Its life-cycle includes more than 40 species of small mammal intermediate hosts. Therefore, host biodiversity losses could be expected to alter transmission. Climate may also have possible impacts on E. multilocularis egg survival. We examined the distribution of human AE across two spatial scales, (i) for continental China and (ii) over the eastern edge of the Tibetan plateau. We tested the hypotheses that human disease distribution can be explained by either the biodiversity of small mammal intermediate host species, or by environmental factors such as climate or landscape characteristics.

Methodology/findings

The distributions of 274 small mammal species were mapped to 967 point locations on a grid covering continental China. Land cover, elevation, monthly rainfall and temperature were mapped using remotely sensed imagery and compared to the distribution of human AE disease at continental scale and over the eastern Tibetan plateau. Infection status of 17,589 people screened by abdominal ultrasound in 2002–2008 in 94 villages of Tibetan areas of western Sichuan and Qinghai provinces was analyzed using generalized additive mixed models and related to epidemiological and environmental covariates. We found that human AE was not directly correlated with small mammal reservoir host species richness, but rather was spatially correlated with landscape features and climate which could confirm and predict human disease hotspots over a 200,000 km² region.

Conclusions/Significance

E. multilocularis transmission and resultant human disease risk was better predicted from landscape features that could support increases of small mammal host species prone to population outbreaks, rather than host species richness. We anticipate that our study may be a starting point for further research wherein landscape management could be used to predict human disease risk and for controlling this zoonotic helminthic.     

Influence of Vectors’ Risk-Spreading Strategies and Environmental Stochasticity on the Epidemiology and Evolution of Vector-Borne Diseases: The Example of Chagas’ Disease

Insects are known to display strategies that spread the risk of encountering unfavorable conditions, thereby decreasing the extinction probability of genetic lineages in unpredictable environments. To what extent these strategies influence the epidemiology and evolution of vector-borne diseases in stochastic environments is largely unknown. In triatomines, the vectors of the parasite Trypanosoma cruzi, the etiological agent of Chagas’ disease, juvenile development time varies between individuals and such variation most likely decreases the extinction risk of vector populations in stochastic environments. We developed a simplified multi-stage vector-borne SI epidemiological model to investigate how vector risk-spreading strategies and environmental stochasticity influence the prevalence and evolution of a parasite. This model is based on available knowledge on triatomine biodemography, but its conceptual outcomes apply, to a certain extent, to other vector-borne diseases. Model comparisons between deterministic and stochastic settings led to the conclusion that environmental stochasticity, vector risk-spreading strategies (in particular an increase in the length and variability of development time) and their interaction have drastic consequences on vector population dynamics, disease prevalence, and the relative short-term evolution of parasite virulence. Our work shows that stochastic environments and associated risk-spreading strategies can increase the prevalence of vector-borne diseases and favor the invasion of more virulent parasite strains on relatively short evolutionary timescales. This study raises new questions and challenges in a context of increasingly unpredictable environmental variations as a result of global climate change and human interventions such as habitat destruction or vector control.