Host mortality, predation and the evolution of parasite virulence

One of the most accepted views in the theoretical literature on virulence evolution is that a parasite's virulence will evolve to higher levels when its host's background mortality rate increases. Surprisingly, however, although many sources of background mortality involve predation, there has not yet been any theoretical research that explicitly considers how the dynamics of this important ecological interaction affects virulence evolution. Here, we consider how predation affects virulence evolution by explicitly introducing a predator into a classical susceptible–infected–susceptible epidemiological model. We find that, contrary to previous predictions, different sources of host mortality affect virulence evolution in different ways. Moreover, the way in which virulence evolution is affected depends on how tightly coupled the predator's dynamics are to the host population, and this can result in somewhat counterintuitive results. For example, indirect ecological effects can cause elevated host mortality to result in the evolution of lower parasite virulence, even if this elevated mortality arises from factors unrelated to predation.     

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.     

On the evolution of virulence and the relationship between various measures of mortality

Smallpox causes roughly 20% mortality whereas chickenpox causes less than 0.1%. Most 'verbal' (i.e. non-mathematical) discussions using a mortality definition of virulence would therefore label smallpox as more virulent. Indeed, the virulence of many diseases is measured using such case mortalities, chi, or related measures such as expected host lifespan, T, or lethal dose, LD(x). But chi, T and LD(x) are only indirectly related to parasite-induced instantaneous mortality rate, alpha, which is the mortality measure used in much of the theory developed to explain virulence evolution. Here I point out that relatively deadly pathogens can actually have lower values of alpha than benign pathogens, demonstrating that alpha does not, by itself, reflect the extent to which a parasite causes host mortality. I present mathematical relationships between alpha and chi, T and LD(x), and use these to demonstrate that predictions about virulence evolution can be qualitatively altered depending upon which measure is used as the definition of virulence. Two simple examples are presented to illustrate this point, one of which demonstrates that the well-cited prediction that virulence should evolve to be higher when disease-independent host mortality increases need not hold. This prediction has been made in terms of parasite-induced instantaneous mortality, alpha, but if virulence is measured using case mortality (or T or LD(x)) then this prediction can easily be reversed. Theoretical and empirical researchers must use compatible mortality measures before a productive exchange between the two can take place, and it is suggested that case mortality (or lethal dose) is best suited as a single (mortality) measure of parasite virulence.     

THE INFLUENCE OF HOST DEMOGRAPHY ON THE EVOLUTION OF VIRULENCE OF A MICROSPORIDIAN GUT PARASITE

It is predicted that host exploitation should evolve to maximize parasite fitness and that virulence (= parasite-induced host mortality) evolves along with the rate of host exploitation. If the life expectancy of a parasite is short, it is expected to evolve a higher rate of host exploitation and therefore higher virulence because the penalty to the parasite for killing the host is reduced. We tested this hypothesis by keeping for 14 months the horizontally transmitted microsporidian parasite Glugoides intestinalis in mono-clonal host cultures (Daphnia magna) under conditions of high and low host background mortality. High host mortality, and thus parasite mortality, was achieved by replacing weekly 70–80% of all hosts in a culture with uninfected hosts from stock cultures (Replacement lines). In the low-mortality treatment no replacement took place. Contrary to our expectation, parasites from the Replacement lines evolved a lower within-host growth rate and virulence than parasites from the Nonreplacement lines. Across lines we found a strong positive correlation between within-host growth rate and virulence. We did further experiments to answer the question why our data did not support the predictions. Sporophorous vesicles (SVs, spore clusters) were smaller in doubly infected than in singly infected host-gut cells, indicating that competition within cells bears costs for the parasite. Due to our experimental protocol, the average life span of infections had been much higher in the Nonreplacement lines. Since the number of parasites inside a host increases with the time since infection, long-lasting infections led to high frequencies of multiply infected host-gut cells. Therefore, we speculated that within-cell competition was more severe in the Nonreplacement lines and may have led to selection for accelerated within-host growth. SVs in the Nonreplacement lines were indeed significantly larger. Our results point out that single-factor explanations for the evolution of virulence can lead to wrong predictions and that multiple infections are an important factor in virulence evolution.     

Bacteriocins, spite and virulence

There has been much interest in using social evolution theory to predict the damage to a host from parasite infection, termed parasite virulence. Most of this work has focused on how high kinship between the parasites infecting a host can select for more prudent exploitation of the host, leading to a negative relationship between virulence and parasite kinship. However, it has also been shown that if parasites can cooperate to overcome the host, then high parasite kinship within hosts can select for greater cooperation and higher growth rates, hence leading to a positive relationship between virulence and parasite kinship. We examine the impact of a spiteful behaviour, chemical (bacteriocin) warfare between microbes, on the evolution of virulence, and find a new relationship: virulence is maximized when the frequency of kin among parasites' social partners is low or high, and is minimized at intermediate values. This emphasizes how biological details can fundamentally alter the qualitative nature of theoretical predictions made by models of parasite virulence.     

Shared control of epidemiological traits in a coevolutionary model of host-parasite interactions

Most models concerning the evolution of a parasite's virulence and its host's resistance assume that each component of the relationship (transmission, virulence, recovery, etc.) is controlled by either the host or the parasite but not by both. We present a model that describes the coevolution of host and parasite, assuming that the rate of transmission or the virulence depends on both genotypes. The evolution of these traits is constrained by trade-offs that account for costs of defense and attack strategies, in line with previous studies on the separate evolution of the host and the parasite. Considering shared control by the host and the parasite in determining the traits of the relationship leads to several novel predictions. First, the host should evolve maximal investment in defense against parasites with an intermediate replication rate. Second, the evolution of the parasite strongly depends on the way the host's defense is described. Third, the coevolutionary process may lead to decreasing the parasite's virulence as a response to a rise in the host's background mortality, contrary to classical predictions.     

Kin selection and the evolution of virulence

Social interactions between conspecific parasites are partly dependent on the relatedness of interacting parasites (kin selection), which, in turn, is predicted to affect the extent of damage they cause their hosts (virulence). High relatedness is generally assumed to favour less competitive interactions, but the relationship between relatedness and virulence is crucially dependent on the social behaviour in question. Here, we discuss the rather limited body of experimental work that addresses how kin-selected social behaviours affect virulence. First, if prudent use of host resources (a form of cooperation) maximizes the transmission success of the parasite population, decreased relatedness is predicted to result in increased host exploitation and virulence. Experimental support for this well-established theoretical result is surprisingly limited. Second, if parasite within-host growth rate is a positive function of cooperation (that is, when individuals need to donate public goods, such as extracellular enzymes), virulence is predicted to increase with increasing relatedness. The limited studies testing this hypothesis are broadly consistent with this prediction. Finally, there is some empirical evidence supporting theory that suggests that spiteful behaviours are maximized at intermediate degrees of relatedness, which, in turn, leads to minimal virulence because of the reduced growth rate of the infecting population. We highlight the need for further thorough experimentation on the role of kin selection in the evolution of virulence and identify additional biological complexities to these simple frameworks.     

The role of defensive symbionts in host–parasite coevolution

Understanding the coevolution of hosts and parasites is a long‐standing goal of evolutionary biology. There is a well‐developed theoretical framework to describe the evolution of host–parasite interactions under the assumption of direct, two‐species interactions, which can result in arms race dynamics or sustained genotype fluctuations driven by negative frequency dependence (Red Queen dynamics). However, many hosts rely on symbionts for defence against parasites. Whilst the ubiquity of defensive symbionts and their potential importance for disease control are increasingly recognized, there is still a gap in our understanding of how symbionts mediate or possibly take part in host–parasite coevolution. Herein we address this question by synthesizing information already available from theoretical and empirical studies. First, we briefly introduce current hypotheses on how defensive mutualisms evolved from more parasitic relationships and highlight exciting new experimental evidence showing that this can occur very rapidly. We go on to show that defensive symbionts influence virtually all important determinants of coevolutionary dynamics, namely the variation in host resistance available to selection by parasites, the specificity of host resistance, and the trade‐off structure between host resistance and other components of fitness. In light of these findings, we turn to the limited theory and experiments available for such three‐species interactions to assess the role of defensive symbionts in host–parasite coevolution. Specifically, we discuss under which conditions the defensive symbiont may take over from the host the reciprocal adaptation with parasites and undergo its own selection dynamics, thereby altering or relaxing selection on the hosts' own immune defences. Finally, we address potential effects of defensive symbionts on the evolution of parasite virulence. This is an important problem for which there is no single, clear‐cut prediction. The selection on parasite virulence resulting from the presence of defensive symbionts in their hosts will depend on the underlying mechanism of defence. We identify the evolutionary predictions for different functional categories of symbiont‐conferred resistance and we evaluate the empirical literature for supporting evidence. We end this review with outstanding questions and promising avenues for future research to improve our understanding of symbiont‐mediated coevolution between hosts and parasites.     

HOST–PARASITE GENETIC INTERACTIONS AND VIRULENCE-TRANSMISSION RELATIONSHIPS IN NATURAL POPULATIONS OF MONARCH BUTTERFLIES

Evolutionary models predict that parasite virulence (parasite-induced host mortality) can evolve as a consequence of natural selection operating on between-host parasite transmission. Two major assumptions are that virulence and transmission are genetically related and that the relative virulence and transmission of parasite genotypes remain similar across host genotypes. We conducted a cross-infection experiment using monarch butterflies and their protozoan parasites from two populations in eastern and western North America. We tested each of 10 host family lines against each of 18 parasite genotypes and measured virulence (host life span) and parasite transmission potential (spore load). Consistent with virulence evolution theory, we found a positive relationship between virulence and transmission across parasite genotypes. However, the absolute values of virulence and transmission differed among host family lines, as did the rank order of parasite clones along the virulence-transmission relationship. Population-level analyses showed that parasites from western North America caused higher infection levels and virulence, but there was no evidence of local adaptation of parasites on sympatric hosts. Collectively, our results suggest that host genotypes can affect the strength and direction of selection on virulence in natural populations, and that predicting virulence evolution may require building genotype-specific interactions into simpler trade-off models.     

A kin selection model for the evolution of virulence.

The costs and benefits of parasite virulence are analysed in an evolutionarily stable strategy (ESS) model. Increased host mortality caused by disease (virulence) reduces a parasite's fitness by damaging its food supply. The fitness costs of high virulence may be offset by the benefits of increased transmission or ability to withstand the host's defences. It has been suggested that multiple infections lead to higher virulence because of competition among parasite strains within a host. A quantitative prediction is given for the ESS virulence rate as a function of the coefficient of relatedness among co-infecting strains. The prediction depends on the quantitative relation between the costs of virulence and the benefits of transmission or avoidance of host defences. The particular mechanisms by which parasites can increase their transmission or avoid host defences also have a key role in the evolution of virulence when there are multiple infections.     

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.     

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.     

Interactions between the parasite's previous and current environment mediate the outcome of parasite infection

The study of parasite virulence has generally focused on the conditions under which virulence is expected to increase or decrease over time and how the interactions between hosts and their environments may mediate the outcome of infection. Recently, parasite traits such as transmission, offspring production, and development have also been shown to be influenced by environmental variation. What is unclear is how variation in the parasite's environment may impact virulence. Recent theory demonstrates that plasticity can promote the evolution of decreased virulence; thus, understanding whether the parasite's environment can mediate virulence can improve predictions regarding the outcome of parasite infection. Here, an obligate mosquito parasite was reared in hosts fed high or low levels of food. Parasite oocysts (offspring) produced in these two host environments were subsequently fed to uninfected hosts. Parasites originating from well-fed hosts were found to be more virulent to these subsequent hosts compared to parasites originating from poorly fed hosts. Additionally, this effect was apparent only when current hosts were food deprived. These results demonstrate that parasite virulence was mediated by a cross-generational effect of the environment and that the overall outcome of infection was modified by variation in both the parasite's and host's environments.     

Parasite transmission modes and the evolution of virulence

A mathematical model is presented that explores the relationship between transmission patterns and the evolution of virulence for horizontally transmitted parasites when only a single parasite strain can infect each host. The model is constructed by decomposing parasite transmission into two processes, the rate of contact between hosts and the probability of transmission per contact. These transmission rate components, as well as the total parasite mortality rate, are allowed to vary over the course of an infection. A general evolutionarily stable condition is presented that partitions the effects of virulence on parasite fitness into three components: fecundity benefits, mortality costs, and morbidity costs. This extension of previous theory allows us to explore the evolutionary consequences of a variety of transmission patterns. I then focus attention on a special case in which the parasite density remains approximately constant during an infection, and I demonstrate two important ways in which transmission modes can affect virulence evolution: by imposing different morbidity costs on the parasite and by altering the scheduling of parasite reproduction during an infection. Both are illustrated with examples, including one that examines the hypothesis that vector-borne parasites should be more virulent than non-vector-borne parasites (Ewald 1994). The validity of this hypothesis depends upon the way in which these two effects interact, and it need not hold in general.     

Within-host population dynamics and the evolution of microparasites in a heterogeneous host population

Abstract Why do parasites harm their hosts? The general understanding is that if the transmission rate and virulence of a parasite are linked, then the parasite must harm its host to maximize its transmission. The exact nature of such trade‐offs remains largely unclear, but for vertebrate hosts it probably involves interactions between a microparasite and the host immune system. Previous results have suggested that in a homogeneous host population in the absence of super‐ or coinfection, within‐host dynamics lead to selection of the parasite with an intermediate growth rate that is just being controlled by the immune system before it kills the host (Antia et al. 1994). In this paper, we examine how this result changes when heterogeneity is introduced to the host population. We incorporate the simplest form of heterogeneity–random heterogeneity in the parameters describing the size of the initial parasite inoculum, the immune response of the host, and the lethal density at which the parasite kills the host. We find that the general conclusion of the previous model holds: parasites evolve some intermediate growth rate. However, in contrast with the generally accepted view, we find that virulence (measured by the case mortality or the rate of parasite‐induced host mortality) increases with heterogeneity. Finally, we link the within‐host and between‐host dynamics of parasites. We show how the parameters for epidemiological spread of the disease can be estimated from the within‐host dynamics, and in doing so examine the way in which trade‐offs between these epidemiological parameters arise as a consequence of the interaction of the parasite and the immune response of the host.     

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.     

Parasite variation and the evolution of virulence in a Daphnia-microparasite system

Understanding genetic relationships amongst the life-history traits of parasites is crucial for testing hypotheses on the evolution of virulence. This study therefore examined variation between parasite isolates (the bacterium Pasteuria ramosa) from the crustacean Daphnia magna. From a single wild-caught infected host we obtained 2 P. ramosa isolates that differed substantially in the mortality they caused. Surprisingly, the isolate causing higher early mortality was, on average, less successful at establishing infections and had a slower growth rate within hosts. The observation that within-host replication rate was negatively correlated with mortality could violate a central assumption of the trade-off hypothesis for the evolution of virulence, but we discuss a number of caveats which caution against premature rejection of the trade-off hypothesis. We sought to test if the characteristics of these parasite isolates were constant across host genotypes in a second experiment that included 2 Daphnia host clones. The relative growth rates of the two parasite isolates did indeed depend on the host genotype (although the rank order did not change). We suggest that testing evolutionary hypotheses for virulence may require substantial sampling of both host and parasite genetic variation, and discuss how selection for virulence may change with the epidemiological state of natural populations and how this can promote genetic variation for virulence.     

Condition-dependent expression of virulence in a trypanosome infecting bumblebees

Parasite virulence affects both the temporal dynamics of host-parasite relationships and the degree to which parasites regulate host populations. If hosts can compensate for parasitism, then parasites may exhibit condition-dependent virulence, with high virulence being seen only when the host is under conditions of stress. Despite their usually low level of virulence, theory suggests that such parasites may still affect host population dynamics. We tested whether a trypanosome intestinal parasite of bumblebees, Crithidia bombi , expresses condition-dependent virulence. Hosts were infected with the parasite and then kept under either favourable or starvation (stressed) conditions. Under favourable conditions the infection caused no mortality, while when hosts were starved the infection increased the host mortality rate by 50%. In addition, we found a parasite-related change in host resource allocation patterns. Infected bees invested relatively more resources into their fat body and less into their reproductive system than did non-infected bees. Whether this reallocation is parasite-driven, to enhance transmission, or a host-response to parasitism, remains unknown.     

Experimental manipulation of immune-mediated disease and its fitness costs for rodent malaria parasites

Background  

Explaining parasite virulence (harm to the host) represents a major challenge for evolutionary and biomedical scientists alike. Most theoretical models of virulence evolution assume that virulence arises as a direct consequence of host exploitation, the process whereby parasites convert host resources into transmission opportunities. However, infection-induced disease can be immune-mediated (immunopathology). Little is known about how immunopathology affects parasite fitness, or how it will affect the evolution of parasite virulence. Here we studied the effects of immunopathology on infection-induced host mortality rate and lifetime transmission potential – key components of parasite fitness – using the rodent malaria model, Plasmodium chabaudi chabaudi.     

Evolution of parasite virulence when host responses cause disease

The trade-off hypothesis of virulence evolution rests on the assumption that infection-induced mortality is a consequence of host exploitation by parasites. This hypothesis lies at the heart of many empirical and theoretical studies of virulence evolution, despite growing evidence that infection-induced mortality is very often a by-product of host immune responses. We extend the theoretical framework of the trade-off hypothesis to incorporate such immunopathology and explore how this detrimental aspect of host defence mechanisms affects the evolution of pathogen exploitation and hence infection-induced mortality. We argue that there are qualitatively different ways in which immunopathology can arise and suggest ways in which empirical studies can tease apart these effects. We show that immunopathology can cause infection-induced mortality to increase or decrease as a result of pathogen evolution, depending on how it covaries with pathogen exploitation strategies and with parasite killing by hosts. Immunopathology is thus an important determinant of whether public and animal health programmes will drive evolution in a clinically beneficial or detrimental direction. Immunopathology complicates our understanding of disease evolution, but can nevertheless be readily accounted for within the framework of the trade-off hypothesis.