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.     

Virulence evolution in response to anti-infection resistance: toxic food plants can select for virulent parasites of monarch butterflies

Host resistance to parasites can come in two main forms: hosts may either reduce the probability of parasite infection (anti-infection resistance) or reduce parasite growth after infection has occurred (anti-growth resistance). Both resistance mechanisms are often imperfect, meaning that they do not fully prevent or clear infections. Theoretical work has suggested that imperfect anti-growth resistance can select for higher parasite virulence by favouring faster-growing and more virulent parasites that overcome this resistance. In contrast, imperfect anti-infection resistance is thought not to select for increased parasite virulence, because it is assumed that it reduces the number of hosts that become infected, but not the fitness of parasites in successfully infected hosts. Here, we develop a theoretical model to show that anti-infection resistance can in fact select for higher virulence when such resistance reduces the effective parasite dose that enters a host. Our model is based on a monarch butterfly-parasite system in which larval food plants confer resistance to the monarch host. We carried out an experiment and showed that this environmental resistance is most likely a form of anti-infection resistance, through which toxic food plants reduce the effective dose of parasites that initiates an infection. We used these results to build a mathematical model to investigate the evolutionary consequences of food plant-induced resistance. Our model shows that when the effective infectious dose is reduced, parasites can compensate by evolving a higher per-parasite growth rate, and consequently a higher intrinsic virulence. Our results are relevant to many insect host-parasite systems, in which larval food plants often confer imperfect anti-infection resistance. Our results also suggest that - for parasites where the infectious dose affects the within-host dynamics - vaccines that reduce the effective infectious dose can select for increased parasite virulence.     

Association between Virulence and Triazole Tolerance in the Phytopathogenic Fungus Mycosphaerella graminicola

Host resistance and synthetic antimicrobials such as fungicides are two of the main approaches used to control plant diseases in conventional agriculture. Although pathogens often evolve to overcome host resistance and antimicrobials, the majority of reports have involved qualitative host – pathogen interactions or antimicrobials targeting a single pathogen protein or metabolic pathway. Studies that consider jointly the evolution of virulence, defined as the degree of damage caused to a host by parasite infection, and antimicrobial resistance are rare. Here we compared virulence and fungicide tolerance in the fungal pathogen Mycosphaerella graminicola sampled from wheat fields across three continents and found a positive correlation between virulence and tolerance to a triazole fungicide. We also found that quantitative host resistance selected for higher pathogen virulence. The possible mechanisms responsible for these observations and their consequences for sustainable disease management are discussed.     

Interaction of a host plant and its holoparasite: effects of previous selection by the parasite

If parasites decrease the fitness of their hosts one could expect selection for host traits (e.g. resistance and tolerance) that decrease the negative effects of parasitic infection. To study selection caused by parasitism, we used a novel study system: we grew host plants (Urtica dioica) that originated from previously parasitized and unparasitized natural populations (four of each) with or without a holoparasitic plant (Cuscuta europaea). Infectivity of the parasite (i.e. qualitative resistance of the host) did not differ between the two host types. Parasites grown with hosts from parasitized populations had lower performance than parasites grown with hosts from unparasitized populations, indicating host resistance in terms of parasite’s performance (i.e. quantitative resistance). However, our results suggest that the tolerance of parasitic infection was lower in hosts from parasitized populations compared with hosts from unparasitized populations as indicated by the lower above‐ground vegetative biomass of the infected host plants from previously parasitized populations.     

Coevolution between parasite virulence and host life-history traits

Epidemiological models generally explore the evolution of parasite life-history traits, namely, virulence and transmission, against a background of constant host life-history traits. However, life-history models have predicted the evolution of host traits in response to parasitism. The coevolution of host and parasite life-history traits remains largely unexplored. We present an epidemiological model, based on resource allocation theory, that provides an analysis of the coevolution between host reproductive effort and parasite virulence. This model allows for hosts with either a fixed (i.e., genetic) or conditional (i.e., a phenotypically plastic) response to parasitism. It also considers superinfections. We show that parasitism always favors increased allocation to host reproduction, but because of epidemiological feedbacks, the evolutionarily stable host reproductive effort does not always increase with parasite virulence. Superinfection drives the evolution of parasite virulence and acts on the evolution of the host through parasite evolution, generally leading to higher host reproductive effort. Coevolution, as opposed to cases where only one of the antagonists evolves, may generate correlations between host and parasite life-history traits across environmental gradients affecting the fecundity or the survival of the host. Our results provide a theoretical framework against which experimental coevolution outcomes or field observations can be contrasted.     

Host heterogeneity is a determinant of competitive exclusion or coexistence in genetically diverse malaria infections

During an infection, malaria parasites compete for limited amounts of food and enemy-free space. Competition affects parasite growth rate, transmission and virulence, and is thus important for parasite evolution. Much evolutionary theory assumes that virulent clones outgrow avirulent ones, favouring the evolution of higher virulence. We infected laboratory mice with a mixture of two Plasmodium chabaudi clones: one virulent, the other avirulent. Using real-time quantitative PCR to track the two parasite clones over the course of the infection, we found that the virulent clone overgrew the avirulent clone. However, host genotype had a major effect on the outcome of competition. In a relatively resistant mouse genotype (C57B1/6J), the avirulent clone was suppressed below detectable levels after 10 days, and apparently lost from the infection. By contrast, in more susceptible mice (CBA/Ca), the avirulent clone was initially suppressed, but it persisted, and during the chronic phase of infection it did better than it did in single infections. Thus, the qualitative outcome of competition depended on host genotype. We suggest that these differences may be explained by different immune responses in the two mouse strains. Host genotype and resistance could therefore play a key role in the outcome of within-host competition between parasite clones and in the evolution of parasite virulence.     

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.     

Genetic variation in resistance, but not tolerance, to a protozoan parasite in the monarch butterfly

Natural selection should strongly favour hosts that can protect themselves against parasites. Most studies on animals so far have focused on resistance, a series of mechanisms through which hosts prevent infection, reduce parasite growth or clear infection. However, animals may instead evolve tolerance, a defence mechanism by which hosts do not reduce parasite infection or growth, but instead alleviate the negative fitness consequences of such infection and growth. Here, we studied genetic variation in resistance and tolerance in the monarch butterfly (Danaus plexippus) to its naturally occurring protozoan parasite, Ophryocystis elektroscirrha. We exposed 560 monarch larvae of 19 different family lines to one of five different parasite inoculation doses (0, 1, 5, 10 and 100 infective spores) to create a range of parasite loads in infected butterflies. We then used two proxies of host fitness (adult lifespan and body mass) to quantify: (i) qualitative resistance (the ability to prevent infection; also known as avoidance or anti-infection resistance); (ii) quantitative resistance (the ability to limit parasite growth upon infection; also known as control or anti-growth resistance); and (iii) tolerance (the ability to maintain fitness with increasing parasite infection intensity). We found significant differences among host families in qualitative and quantitative resistance, indicating genetic variation in resistance. However, we found no genetic variation in tolerance. This may indicate that all butterflies in our studied population have evolved maximum tolerance, as predicted by some theoretical models.     

Epidemiology of a Daphnia-multiparasite system and its implications for the red queen

The Red Queen hypothesis can explain the maintenance of host and parasite diversity. However, the Red Queen requires genetic specificity for infection risk (i.e., that infection depends on the exact combination of host and parasite genotypes) and strongly virulent effects of infection on host fitness. A European crustacean (Daphnia magna)--bacterium (Pasteuria ramosa) system typifies such specificity and high virulence. We studied the North American host Daphnia dentifera and its natural parasite Pasteuria ramosa, and also found strong genetic specificity for infection success and high virulence. These results suggest that Pasteuria could promote Red Queen dynamics with D. dentifera populations as well. However, the Red Queen might be undermined in this system by selection from a more common yeast parasite (Metschnikowia bicuspidata). Resistance to the yeast did not correlate with resistance to Pasteuria among host genotypes, suggesting that selection by Metschnikowia should proceed relatively independently of selection by Pasteuria.     

Contrasting consequences of different defence strategies in a natural multihost–parasite system

Hosts counteract infections using two distinct defence strategies, resistance (reduction in pathogen fitness) and tolerance (limitation of infection damage). These strategies have been minimally investigated in multi-host systems, where they may vary across host species, entailing consequences both for hosts (virulence) and parasites (transmission). Comprehending the interplay among resistance, tolerance, virulence and parasite success is highly relevant for our understanding of the ecology and evolution of infectious and parasitic diseases. Our work investigated the interaction between an insect parasite and its most common bird host species, focusing on two relevant questions: (i) are defence strategies different between main and alternative hosts and, (ii) what are the consequences (virulence and parasite success) of different defence strategies? We conducted a matched field experiment and longitudinal studies at the host and the parasite levels under natural conditions, using a system comprising Philornis torquans flies and three bird hosts – the main host and two of the most frequently used alternative hosts. We found that main and alternative hosts have contrasting defence strategies, which gave rise in turn to contrasting virulence and parasite success. In the main bird host, minor loss of fitness, no detectable immune response, and high parasite success suggest a strategy of high tolerance and negligible resistance. Alternative hosts, on the contrary, resisted by mounting inflammatory responses, although with very different efficiency, which resulted in highly dissimilar parasite success and virulence. These results show clearly distinct defence strategies between main and alternative hosts in a natural multi-host system. They also highlight the importance of defence strategies in determining virulence and infection dynamics, and hint that defence efficiency is a crucial intervening element in these processes.     

Cost of strepsipteran macroparasitism for immature wasps: does sociality modulate virulence?

An important factor modulating parasite virulence is the level of extrinsic mortality experienced by hosts. Where it is high, parasites are expected to grow or reproduce quickly to complete their lifecycle before their host is killed, whereas virulence is expected to be less under low extrinsic mortality, where growth/reproduction can be slower. A prominent example of a low mortality environment for parasites are immature social insects. Here we examined the cost of parasitism, i.e. virulence, experienced by larval and pupal stages of Polistes wasps following infection by endoparasitic Strepsiptera (under starvation conditions). We found that there was no difference in virulence between infected and uninfected individuals for the seven days following infection; either measured as host mortality or mass loss. Likewise, there was no observed cost of parasitism during the first seven days of the pupal stage of the host. Growth of the endoparasitic stages appeared the same between starved laboratory individuals and field caught samples. Strepsipteran parasites apparently enter a lag phase until the later stages of host pupal development, which we speculate reduces the negative impact of parasitism during the hosts' critical developmental stages. Our results highlight the need for further inquiry into the influence of sociality upon the evolution of parasite virulence.     

Genetic variation in a host-parasite association: potential for coevolution and frequency-dependent selection

Abstract.— Models of host‐parasite coevolution assume the presence of genetic variation for host resistance and parasite infectivity, as well as genotype‐specific interactions. We used the freshwater crustacean Daphnia magna and its bacterial microparasite Pasteuria ramosa to study genetic variation for host susceptibility and parasite infectivity within each of two populations. We sought to answer the following questions: Do host clones differ in their susceptibility to parasite isolates? Do parasite isolates differ in their ability to infect different host clones? Are there host clone‐parasite isolate interactions? The analysis revealed considerable variation in both host resistance and parasite infectivity. There were significant host clone‐parasite isolate interactions, such that there was no single host clone that was superior to all other clones in the resistance to every parasite isolate. Likewise, there was no parasite isolate that was superior to all other isolates in infectivity to every host clone. This form of host clone‐parasite isolate interaction indicates the potential for coevolution based on frequency‐dependent selection. Infection success of original host clone‐parasite isolate combinations (i.e., those combinations that were isolated together) was significantly higher than infection success of novel host clone‐parasite isolate combinations (i.e., those combinations that were created in the laboratory). This finding is consistent with the idea that parasites track specific host genotypes under natural conditions. In addition, correspondence analysis revealed that some host clones, although distinguishable with neutral genetic markers, were susceptible to the same set of parasite isolates and thus probably shared resistance genes.     

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.     

Virulence reaction norms across a food gradient

Host-parasite interactions involve competition for nutritional resources between hosts and the parasites growing within them. Consuming part of a host's resources is one cause of a parasite's virulence, i.e. part of the fitness cost imposed on the host by the parasite. The influence of a host's nutritional conditions on the virulence of a parasite was experimentally tested using the mosquito Aedes aegypti and the microsporidian parasite Vavraia culicis. A condition-dependent expression of virulence was found and a positive relation between virulence and transmissibility was established. Spore production was positively influenced by host food availability, indicating that the parasite's within-host growth is limited by host condition. We also investigated how the fitness of each partner varied across the nutritional gradient and demonstrated that the sign of the correlation between host fitness and parasite fitness depended on the amount of nutritional resources available to the host.     

HOST LIFE HISTORY AND THE EVOLUTION OF PARASITE VIRULENCE

Abstract.— We present a general epidemiological model of host‐parasite interactions that includes various forms of superinfection. We use this model to study the effects of different host life‐history traits on the evolution of parasite virulence. In particular, we analyze the effects of natural host death rate on the evolutionarily stable parasite virulence. We show that, contrary to classical predictions, an increase in the natural host death rate may select for lower parasite virulence if some form of superinfection occurs. This result is in agreement with the experimental results and the verbal argument presented by Ebert and Mangin (1997). This experiment is discussed in the light of the present model. We also point out the importance of superinfections for the effect of nonspecific immunity on the evolution of virulence. In a broader perspective, this model demonstrates that the occurrence of multiple infections may qualitatively alter classical predictions concerning the effects of various host life‐history traits on the evolution of parasite virulence.     

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.     

Host-parasite coevolution in a multilocus gene-for-gene system.

This paper examines a mathematical model for the coevolution of parasite virulence and host resistance under a multilocus gene-for-gene interaction. The degrees of parasite virulence and host resistance show coevolutionary cycles for sufficiently small costs of virulence and resistance. Besides these coevolutionary cycles of a longer period, multilocus genotype frequencies show complex fluctuations over shorter periods. All multilocus genotypes are maintained within host and parasite classes having the same number of resistant/virulent alleles and their frequencies fluctuate with approximately equally displaced phases. If either the cost of virulence or the number of resistance loci is larger then a threshold, the host maintains the static polymorphism of singly (or doubly or more, depending on the cost of resistance) resistant genotypes and the parasite remains universally avirulent. In other words, host polymorphism can prevent the invasion of any virulent strain in the parasite. Thus, although assuming an empirically common type of asymmetrical gene-for-gene interaction, both host and parasite populations can maintain polymorphism in each locus and retain complex fluctuations. Implications for the red queen hypothesis of the evolution of sex and the control of multiple drug resistance are discussed.     

The evolution of parasite host range in heterogeneous host populations

Theory on the evolution of niche width argues that resource heterogeneity selects for niche breadth. For parasites, this theory predicts that parasite populations will evolve, or maintain, broader host ranges when selected in genetically diverse host populations relative to homogeneous host populations. To test this prediction, we selected the bacterial parasite Serratia marcescens to kill Caenorhabditis elegans in populations that were genetically heterogeneous (50% mix of two experimental genotypes) or homogeneous (100% of either genotype). After 20 rounds of selection, we compared the host range of selected parasites by measuring parasite fitness (i.e. virulence, the selected fitness trait) on the two focal host genotypes and on a novel host genotype. As predicted, heterogeneous host populations selected for parasites with a broader host range: these parasite populations gained or maintained virulence on all host genotypes. This result contrasted with selection in homogeneous populations of one host genotype. Here, host range contracted, with parasite populations gaining virulence on the focal host genotype and losing virulence on the novel host genotype. This pattern was not, however, repeated with selection in homogeneous populations of the second host genotype: these parasite populations did not gain virulence on the focal host genotype, nor did they lose virulence on the novel host genotype. Our results indicate that host heterogeneity can maintain broader host ranges in parasite populations. Individual host genotypes, however, vary in the degree to which they select for specialization in parasite populations.     

Evolution of host resistance and trade‐offs between virulence and transmission potential in an obligately killing parasite

Standard epidemiological theory predicts that parasites, which continuously release propagules during infection, face a trade‐off between virulence and transmission. However, little is known how host resistance and parasite virulence change during coevolution with obligate killers. To address this question we have set up a coevolution experiment evolving Nosema whitei on eight distinct lines of Tribolium castaneum. After 11 generations we conducted a time‐shift experiment infecting both the coevolved and the replicate control host lines with the original parasite source, and coevolved parasites from generation 8 and 11. We found higher survival in the coevolved host lines than in the matching control lines. In the parasite populations, virulence measured as host mortality decreased during coevolution, while sporeload stayed constant. Both patterns are compatible with adaptive evolution by selection for resistance in the host and by trade‐offs between virulence and transmission potential in the parasite.     

Genetics and evolution of parasites and hosts: some comments

We provide a brief commentary on aspects of the analysis of the genetics and evolution of malaria parasites. Any attempt to understand the nature and manifestations of an infectious disease requires an understanding of the genetics of both pathogen and host. The outcome of a malaria infection, i.e. whether it is asymptomatic, mild, severe or causes cerebral malaria, is due to a complex interaction between the products of parasite and host genes. In general terms, genes in the parasite determine its ability to infect the host, its virulence, etc., while host genes will determine resistance or susceptibility to infection. More than this, however, genetics is about the spread of genes in populations, how they mutate and recombine to produce novel genotypes, and how the parasite and its hosts co-evolve with changing environments. This is a complex subject, and we present some discussion of a few aspects of its analysis.