Multiple infections, immune dynamics, and the evolution of virulence

Understanding the effect of multiple infections is essential for the prediction (and eventual control) of virulence evolution. Some theoretical studies have considered the possibility that several strains coexist in the same host (coinfection), but few have taken their within-host dynamics explicitly into account. Here, we develop a nested approach based on a simple model for the interaction of parasite strains with their host's immune system. We study virulence evolution by linking the within-host dynamics to an epidemiological framework that incorporates multiple infections. Our model suggests that antigenically similar parasite strains cannot coexist in the long term inside a host. We also find that the optimal level of virulence increases with the efficiency of multiple infections. Finally, we notice that coinfections create heterogeneity in the host population (with susceptible hosts and infected hosts), which can lead to evolutionary branching in the parasite population and the emergence of a hypervirulent parasite strategy. We interpret this result as a parasite specialization to the infectious state of the hosts. Our study has experimental and theoretical implications in a virulence management perspective.     

Multiple infections and the evolution of virulence

Infections that consist of multiple parasite strains or species are common in the wild and are a major public health concern. Theory suggests that these infections have a key influence on the evolution of infectious diseases and, more specifically, on virulence evolution. However, we still lack an overall vision of the empirical support for these predictions. We argue that within‐host interactions between parasites largely determine how virulence evolves and that experimental data support model predictions. Then, we explore the main limitation of the experimental study of such ‘mixed infections’, which is that it draws conclusions on evolutionary outcomes from studies conducted at the individual level. We also discuss differences between coinfections caused by different strains of the same species or by different species. Overall, we argue that it is possible to make sense out of the complexity inherent to multiple infections and that experimental evolution settings may provide the best opportunity to further our understanding of virulence evolution.     

Multiple infections,kin selection and the evolutionary epidemiology of parasite traits

The coinfection of a host by several parasite strains is known to affect selective pressures on parasite strategies of host exploitation. I present a general model of coinfections that ties together kin selection models of virulence evolution and epidemiological models of multiple infections. I derive an analytical expression for the invasion fitness of a rare mutant in a population with an arbitrary distribution of the multiplicity of infection (MOI) across hosts. When a single mutation affects parasite strategies in all MOI classes, I show that the evolutionarily stable level of virulence depends on a demographic average of within‐host relatedness across all host classes. This generalization of previous kin selection results requires that within‐host parasite densities do not vary between hosts. When host exploitation strategies are allowed to vary across classes, I show that the strategy of host exploitation in a focal MOI class depends on the relative magnitudes of parasite reproductive values in the focal class and in the next. Thus, in contrast to previous findings, lower within‐host relatedness in competitive parasite interactions can potentially correspond to either higher or lower levels of virulence.     

How parasite interaction strategies alter virulence evolution in multi‐parasite communities

The majority of organisms host multiple parasite species, each of which can interact with hosts and competitors through a diverse range of direct and indirect mechanisms. These within‐host interactions can directly alter the mortality rate of coinfected hosts and alter the evolution of virulence (parasite‐induced host mortality). Yet we still know little about how within‐host interactions affect the evolution of parasite virulence in multi‐parasite communities. Here, we modeled the virulence evolution of two coinfecting parasites in a host population in which parasites interacted through cross immunity, immune suppression, immunopathology, or spite. We show (1) that these within‐host interactions have different effects on virulence evolution when all parasites interact with each other in the same way versus when coinfecting parasites have unique interaction strategies, (2) that these interactions cause the evolution of lower virulence in some hosts, and higher virulence in other hosts, depending on the hosts infection status, and (3) that for cross immunity and spite, whether parasites increase or decrease the evolutionarily stable virulence in coinfected hosts depended on interaction strength. These results improve our understanding of virulence evolution in complex parasite communities, and show that virulence evolution must be understood at the community scale.     

PARASITE CO‐TRANSMISSION AND THE EVOLUTIONARY EPIDEMIOLOGY OF VIRULENCE

Hosts are often co‐infected by several parasite genotypes of the same species or even by different species and this is known to affect virulence evolution. However, epidemiological models typically assume that only one of the co‐infecting strains can be transmitted at the same time, which is often at odds with the observed biology. Here, I study the effect of co‐transmission on virulence evolution in a case where parasites compete for host resources. For co‐infections by strains of the same species, increased co‐transmission selects for less virulent strains. This is because co‐transmission aligns the interests of co‐infecting strains, thus decreasing the selective pressure for increased within‐host competitiveness. For co‐infection caused by different parasite species, the evolutionary outcome depends on the respective virulence of the two parasite species. Finally, I investigate asymmetric scenarios, for example that of plant viruses that require “helper” molecules produced by viruses from another species to be transmitted. These results show that even if parasite strains compete for host resources, the prevalence of co‐infections can be a poor predictor of virulence evolution.     

The evolution of parasite virulence, superinfection, and host resistance

We analyze the evolutionary consequences of host resistance (the ability to decrease the probability of being infected by parasites) for the evolution of parasite virulence (the deleterious effect of a parasite on its host). When only single infections occur, host resistance does not affect the evolution of parasite virulence. However, when superinfections occur, resistance tends to decrease the evolutionarily stable (ES) level of parasite virulence. We first study a simple model in which the host does not coevolve with the parasite (i.e., the frequency of resistant hosts is independent of the parasite). We show that a higher proportion of resistant host decreases the ES level of parasite virulence. Higher levels of the efficiency of host resistance, however, do not always decrease the ES parasite virulence. The implications of these results for virulence management (evolutionary consequences of public health policies) are discussed. Second, we analyze the case where host resistance is allowed to coevolve with parasite virulence using the classical gene-for-gene (GFG) model of host-parasite interaction. It is shown that GFG coevolution leads to lower parasite virulence (in comparison with a fully susceptible host population). The model clarifies and relates the different components of the cost of parasitism: infectivity (ability to infect the host) and virulence (deleterious effect) in an evolutionary perspective.     

Vaccine-driven evolution of parasite virulence and immune evasion in age-structured population: the case of pertussis

Despite enormous success of mass immunization programs in reducing incidence of infectious diseases, vaccine-escape strains have emerged perhaps as a consequence of strong selection pressures exerted on parasites by vaccines. Pertussis presents a well-documented example. As a childhood infection, it exhibits age-specific transmission biased to children. Assuming different transmission rates between children and adults, I study, by means of an age-structured epidemic model, evolutionary dynamics of parasite virulence in a vaccinated population. I find that the age-structure does not affect the evolutionary dynamics of parasite virulence. Also, based on empirical data reporting antigenic divergence with vaccine strains and mutations in virulence-associated genes in pertussis populations, I allow for parallel occurrence of mutations in parasite virulence and associated immune evasion. I conclude that this simultaneous adaptation of both traits may substantially alter the evolutionary course of the parasite. In particular, higher values of virulence are favoured once the parasite is able to evade the transmission-blocking vaccine-induced immunity. On the other hand, lower values of virulence are selected for once the parasite evolves the ability to evade the virulence-blocking vaccine-induced immunity. I emphasize the importance of multi-trait evolution to assess the direction of parasite adaptation more accurately.     

Coevolution of virulence and immunosuppression in multiple infections

Many components of host–parasite interactions have been shown to affect the way virulence (i.e. parasite‐induced harm to the host) evolves. However, coevolution of multiple parasite traits is often neglected. We explore how an immunosuppressive adaptation of parasites affects and coevolves with virulence in multiple infections. Applying the adaptive dynamics framework to epidemiological models with coinfection, we show that immunosuppression is a double‐edged sword for the evolution of virulence. On one hand, it amplifies the adaptive benefit of virulence by increasing the abundance of coinfections through epidemiological feedbacks. On the other hand, immunosuppression hinders host recovery, prolonging the duration of infection and elevating the cost of killing the host (as more opportunities for transmission will be forgone if the host dies). The balance between the cost and benefit of immunosuppression varies across different background mortality rates of hosts. In addition, we find that immunosuppression evolution is influenced considerably by the precise trade‐off shape determining the effect of immunosuppression on host recovery and susceptibility to further infection. These results demonstrate that the evolution of virulence is shaped by immunosuppression while highlighting that the evolution of immune evasion mechanisms deserves further research attention.     

Does multiple infection select for raised virulence?

Classical models of virulence evolution conclude that the increased competition favoured by multiple infection will select for increasing consumption and deterioration of the host resource, or 'virulence'. However, recent empirical and theoretical studies suggest that this view of virulence has some shortcomings. Here, we argue that the evolutionary consequences of multiple infection depend critically on whether the exploitation rate of an individual parasite is governed directly by the behaviour of the individual, or whether it is limited by the collective behaviour of the coinfecting group. We illustrate that, depending on the mechanistic details of exploitation, multiple infection can select for reduced virulence.     

Priority effects within coinfected hosts can drive unexpected population‐scale patterns of parasite prevalence

Organisms are frequently coinfected by multiple parasite strains and species, and interactions between parasites within hosts are known to influence parasite prevalence and diversity, as well as epidemic timing. Importantly, interactions between coinfecting parasites can be affected by the order in which they infect hosts (i.e. within‐host priority effects). In this study, we use a single‐host, two‐pathogen, SI model with environmental transmission to explore how within‐host priority effects scale up to alter host population‐scale infection patterns. Specifically, we ask how parasite prevalence changes in the presence of different types of priority effects. We consider two scenarios without priority effects and four scenarios with priority effects where there is either an advantage or a disadvantage to being the first to infect in a coinfected host. Models without priority effects always predict negative relationships between the prevalences of both parasites. In contrast, models with priority effects can yield unimodal prevalence relationships where the prevalence of a focal parasite is minimized or maximized at intermediate prevalences of a coinfecting parasite. The mechanism behind this pattern is that as the prevalence of the coinfecting parasite increases, most infections of the focal parasite change from occurring as solo infections, to first arrival coinfections, to second arrival coinfections. The corresponding changes in parasite fitness as the focal parasite moves from one infection class to another then map to changes in focal parasite prevalence. Further, we found that even when parasites interact negatively within a host, they still can have positive prevalence relationships at the population scale. These results suggest that within‐host priority effects can change host population‐scale infection patterns in systematic (and initially counterintuitive) ways, and that taking them into account may improve disease forecasting in coinfected populations.     

Evolution of virulence in a heterogeneous host population

Abstract.— There is a large body of theoretical studies that investigate factors that affect the evolution of virulence, that is parasite-induced host mortality. In these studies the host population is assumed to be genetically homogeneous. However, many parasites have a broad range of host types they infect, and trade-offs between the parasite virulence in different host types may exist. The aim of this paper is to study the effect of host heterogeneity on the evolution of parasite virulence. By analyzing a simple model that describes the replication of different parasite strains in a population of two different host types, we determine the optimal level of virulence in both host types and find the conditions under which strains that specialize in one host type dominate the parasite population. Furthermore, we show that intrahost evolution of the parasite during an infection may lead to stable polymorphisms and could introduce evolutionary branching in the parasite population.     

A general theory for the evolutionary dynamics of virulence

Most theory on the evolution of virulence is based on a game-theoretic approach. One potential shortcoming of this approach is that it does not allow the prediction of the evolutionary dynamics of virulence. Such dynamics are of interest for several reasons: for experimental tests of theory, for the development of useful virulence management protocols, and for understanding virulence evolution in situations where the epidemiological dynamics never reach equilibrium and/or when evolutionary change occurs on a timescale comparable to that of the epidemiological dynamics. Here we present a general theory similar to that of quantitative genetics in evolutionary biology that allows for the easy construction of models that include both within-host mutation as well as superinfection and that is capable of predicting both the short- and long-term evolution of virulence. We illustrate the generality and intuitive appeal of the theory through a series of examples showing how it can lead to transparent interpretations of the selective forces governing virulence evolution. It also leads to novel predictions that are not possible using the game-theoretic approach. The general theory can be used to model the evolution of other pathogen traits as well.     

Host resistance and pathogen aggressiveness are key determinants of coinfection in the wild

Coinfection, whereby the same host is infected by more than one pathogen strain, may favor faster host exploitation rates as strains compete for the same limited resources. Hence, coinfection is expected to have major consequences for pathogen evolution, virulence, and epidemiology. Theory predicts genetic variation in host resistance and pathogen infectivity to play a key role in how coinfections are formed. The limited number of studies available has demonstrated coinfection to be a common phenomenon, but little is known about how coinfection varies in space, and what its determinants are. Our aim is to understand how variation in host resistance and pathogen infectivity and aggressiveness contribute to how coinfections are formed in the interaction between fungal pathogen Podosphaera plantaginis and Plantago lanceolata. Our phenotyping study reveals that more aggressive strains are more likely to form coinfections than less aggressive strains in the natural populations. In the natural populations most of the variation in coinfection is found at the individual plant level, and results from a common garden study confirm the prevalence of coinfection to vary significantly among host genotypes. These results show that genetic variation in both the host and pathogen populations are key determinants of coinfection in the wild.     

Evolutionary branching of virulence in a single-infection model

This study explores the evolutionary dynamics of pathogen virulence in a single-infection model with density-dependent mortality. Although virulence is not an adaptation of the pathogen per se, it is generally believed to be an inevitable by-product of a pathogen's need to propagate and transmit to new hosts: an increase in virulence will parallel an increase in transmission efficacy. The exact characteristics of the trade-off curve defined by this relationship are important with respect to possible evolutionary scenarios. We conduct a critical function analysis, a method that exposes the evolutionary outcome resulting from trade-offs of arbitrary shape, and find that this simple model can display a wide variety of evolutionary dynamics; comprising multiple stable attractors, evolutionary repellors, and most notably, evolutionary branching points. We identify the conditions under which the different evolutionary outcomes are realised. Our analysis furthermore considers the evolution of coexisting strains, and identifies the trade-off characteristics that will support an evolutionarily stable dimorphic state. We find that an evolutionarily stable dimorphism may exist also in the absence of a branching point in the monomorphic state. The analysis reveals that an evolutionarily stable dimorphism will always be attracting and that no further branching is possible under this model. We discuss our results in relation to the dimension of the environmental feedback inherent in the model, and to results from previous studies and models of evolution of virulence.     

Coevolution of parasite virulence and host life history

Most models about the evolutionary interactions between a parasite's virulence and its host's life history neglect two potentially important aspects: epidemiological and coevolutionary feedback. We emphasize their importance by presenting models that describe the coevolution of a semelparous host's age at reproduction and a parasite's virulence in different environmental conditions. In particular, we first show that an epidemiological feedback will lead to a nonmonotonic response of the host's age at reproduction as virulence increases. We then show that the coevolutionary pressure on virulence can lead to complex associations between the host's life history and the parasite's virulence, which would not be expected with more traditional models of host or parasite evolution. Thus, for example, a high mortality rate of the host favours avirulent parasites and late reproduction of the host when the environmental conditions allow the host to grow rapidly, but early reproduction and high virulence when growth is slow.     

Dynamics of multiple infection and within-host competition in genetically diverse malaria infections

Within-host competition between coinfecting parasite strains shapes the evolution of parasite phenotypes such as virulence and drug resistance. Although this evolution has a strong theoretical basis, within-host competition has rarely been studied experimentally, particularly in medically relevant pathogens with hosts that have pronounced specific and nonspecific immune responses against coinfecting strains. We investigated multiple infection in malaria, using two pairs of genetically distinct clones of the rodent malaria Plasmodium chabaudi in mice. Clones were inoculated into mice simultaneously or 3 or 11 days apart, and population sizes were tracked using immunofluorescence or quantitative polymerase chain reaction. In all experiments, at least one of the two clones suffered strong competitive suppression, probably through both resource- and immune-mediated (apparent) competition. Clones differed in intrinsic competitive ability, but prior residency was also an important determinant of competitive outcome. When clones infected mice first, they did not suffer from competition, but they did when infecting mice at the same time or after their competitor, more so the later they infected their host. Consequently, clones that are competitively inferior in head-to-head competition can be competitively superior if they infect hosts first. These results are discussed in the light of strain-specific immunity, drug resistance, and virulence evolution theory.     

IS HIV SHORT‐SIGHTED? INSIGHTS FROM A MULTISTRAIN NESTED MODEL

An important component of pathogen evolution at the population level is evolution within hosts. Unless evolution within hosts is very slow compared to the duration of infection, the composition of pathogen genotypes within a host is likely to change during the course of an infection, thus altering the composition of genotypes available for transmission as infection progresses. We develop a nested modeling approach that allows us to follow the evolution of pathogens at the epidemiological level by explicitly considering within‐host evolutionary dynamics of multiple competing strains and the timing of transmission. We use the framework to investigate the impact of short‐sighted within‐host evolution on the evolution of virulence of human immunodeficiency virus (HIV), and find that the topology of the within‐host adaptive landscape determines how virulence evolves at the epidemiological level. If viral reproduction rates increase significantly during the course of infection, the viral population will evolve a high level of virulence even though this will reduce the transmission potential of the virus. However, if reproduction rates increase more modestly, as data suggest, our model predicts that HIV virulence will be only marginally higher than the level that maximizes the transmission potential of the virus.     

Local host competition in the evolution of virulence

The evolution of parasite life histories should usually have correlated effects on host survivorship and/or reproductive success. For example, parasites that reproduce more rapidly might be expected to cause greater reductions in host fitness. Important theoretical advances have recently been made on virulence evolution, but the results are not always consistent. Here I compare two models [ Q. Rev. Biol. 71 (1996) 37 ; Q. Rev. Biol. 75 (2000) 261 ] on the evolution of virulence that get qualitatively different results with respect to the effects of coinfection. I also construct a third model that attempts to connect these two formulations. The results suggest that parasite growth rates should increase as local host competition increases, unless relatedness is at equilibrium. In addition, the qualitative effect of adding coinfections on parasite growth rates depends critically on how the number of coinfections affects transmission success.     

Differences in accumulation and virulence determine the outcome of competition during Tobacco etch virus coinfection

Understanding the evolution of virulence for RNA viruses is essential for developing appropriate control strategies. Although it has been usually assumed that virulence is a consequence of within-host replication of the parasite, viral strains may be highly virulent without experiencing large accumulation as a consequence of immunopathological host responses. Using two strains of Tobacco etch potyvirus (TEV) that show a negative relationship between virulence and accumulation rate, we first explored the evolution of virulence and fitness traits during simple and mixed infections. Short-term evolution experiments initiated with each strain independently confirmed the genetic and evolutionary stability of virulence and viral load, although infectivity significantly increased for both strains. Second, competition experiments between hypo- and hypervirulent TEV strains have shown that the outcome of competition is driven by differences in replication rate. A simple mathematical model has been developed to analyze the dynamics of these two strains during coinfection. The model qualitatively reproduced the experimental results using biologically meaningful parameters. Further analyses of the model also revealed a wide parametric region in which a low-fitness but hypovirulent virus can still outcompete a high-fitness but hypervirulent one. These results provide additional support to the observation that virulence and within-host replication may not necessarily be strongly tied in plant RNA viruses.     

Host sexual dimorphism affects the outcome of within‐host pathogen competition

Natural infections often consist of multiple pathogens of the same or different species. When coinfections occur, pathogens compete for access to host resources and fitness is determined by how well a pathogen can reproduce compared to its competitors. Yet not all hosts provide the same resource pool. Males and females, in particular, commonly vary in both their acquisition of resources and investment in immunity, but their ability to modify any competition between different pathogens remains unknown. Using the Daphnia magna–Pasteuria ramosa model system, we exposed male and female hosts to either a single genotype infection or coinfections consisting of two pathogen genotypes of varying levels of virulence. We found that coinfections within females favored the transmission of the more virulent pathogen genotype, whereas coinfections within male hosts resulted in equal transmission of competing pathogen genotypes. This contrast became less pronounced when the least virulent pathogen was able to establish an infection first, suggesting that the influence of host sex is shaped by priority effects. We suggest that sex is a form of host heterogeneity that may influence the evolution of virulence within coinfection contexts and that one sex may be a reservoir for pathogen genetic diversity in nature.