The role of ecological feedbacks in the evolution of host defence: what does theory tell us?

Hosts have evolved a diverse range of defence mechanisms in response to challenge by infectious organisms (parasites and pathogens). Whether defence is through avoidance of infection, control of the growth of the parasite once infected, clearance of the infection, tolerance to the disease caused by infection or innate and/or acquired immunity, it will have important implications for the population ecology (epidemiology) of the host-parasite interaction. As a consequence, it is important to understand the evolutionary dynamics of defence in the light of the ecological feedbacks that are intrinsic to the interaction. Here, we review the theoretical models that examine how these feedbacks influence the nature and extent of the defence that will evolve. We begin by briefly comparing different evolutionary modelling approaches and discuss in detail the modern game theoretical approach (adaptive dynamics) that allows ecological feedbacks to be taken into account. Next, we discuss a number of models of host defence in detail and, in particular, make a distinction between 'resistance' and 'tolerance'. Finally, we discuss coevolutionary models and the potential use of models that include genetic and game theoretical approaches. Our aim is to review theoretical approaches that investigate the evolution of defence and to explain how the type of defence and the costs associated with its acquisition are important in determining the level of defence that evolves.     

HOW SPECIFICITY AND EPIDEMIOLOGY DRIVE THE COEVOLUTION OF STATIC TRAIT DIVERSITY IN HOSTS AND PARASITES

There is typically considerable variation in the level of infectivity of parasites and the degree of resistance of hosts within populations. This trait variation is critical not only to the evolutionary dynamics but also to the epidemiology, and potentially the control of infectious disease. However, we lack an understanding of the processes that generate and maintain this trait diversity. We examine theoretically how epidemiological feedbacks and the characteristics of the interaction between host types and parasites strains determine the coevolution of host–parasite diversity. The interactions include continuous characterizations of the key phenotypic features of classic gene‐for‐gene and matching allele models. We show that when there are costs to resistance in the hosts and infectivity in the parasite, epidemiological feedbacks may generate diversity but this is limited to dimorphism, often of extreme types, in a broad range of realistic infection scenarios. For trait polymorphism, there needs to be both specificity of infection between host types and parasite strains as well as incompatibility between particular strains and types. We emphasize that although the high specificity is well known to promote temporal “Red Queen” diversity, it is costs and combinations of hosts and parasites that cannot infect that will promote static trait diversity.     

Host lifespan and the evolution of resistance to multiple parasites

Hosts are typically challenged by multiple parasites, but to date theory on the evolution of resistance has mainly focused on single infections. We develop a series of models that examine the impact of multiple parasites on the evolution of resistance under the assumption that parasites coexist at the host population scale as a consequence of superinfection. In this way, we are able to explicitly examine the impact of ecological dynamics on the evolutionary outcome. We use our models to address a key question of how host lifespan affects investment in resistance to multiple parasites. We show that investment in costly resistance depends on the specificity of the immune response and on whether or not the focal parasite leads to more acute infection than the co‐circulating parasite. A key finding is that investment in resistance always increases as the immune response becomes more general independently of whether it is the focal or the co‐circulating parasite that exploits the host most aggressively. Long‐lived hosts always invest more than short‐lived hosts in both general resistance and resistance that is specific to relatively acute focal parasites. However, for specific resistance to parasites that are less acute than co‐circulating parasites it is the short‐lived hosts that are predicted to invest most. We show that these results apply whatever the mode of defence, that is whether it is through avoidance or through increased recovery, with or without acquired immunity, or through acquired immunity itself. As a whole, our results emphasize the importance of considering multiple parasites in determining optimal immune investment in eco‐evolutionary systems.     

The importance of who infects whom: the evolution of diversity in host resistance to infectious disease

Variation for resistance to infectious disease is ubiquitous and critical to host and parasite evolution and to disease impact, spread and control. However, the processes that generate and maintain this diversity are not understood. We examine how ecological feedbacks generate diversity in host defence focussing on when polymorphism can evolve without co-evolution of the parasite. Our key result is that when there is heritable variation in hosts in both their transmissibility and susceptibility along with costs to resistance, there is the possibility of the evolution of polymorphism. We argue that a wide range of behavioural or physiological mechanisms may lead to relationships between transmissibility and susceptibility that generate diversity. We illustrate this by showing that a tendency for higher contacts between related individuals leads to polymorphism. Only dimorphisms can evolve when infection is determined only by an individuals' susceptibility or when transmissibility and susceptibility are simply positively or negatively correlated.     

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.     

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.     

No evidence for specificity between host and parasite genotypes in experimental Strongyloides ratti (Nematoda) infections

A key requirement for several theories involving the evolution of sex and sexual selection is a specificity between host and parasite genotypes, i.e. the resistance of particular host genotypes to particular parasite genotypes and the infectivity of particular parasite genotypes for particular host genotypes. Determining the scope and nature of any such specificity is also of applied relevance, since any specificity for different parasite genotypes to infect particular host genotypes may affect the level of protection afforded by vaccination, the efficacy of selective breeding of livestock for parasite resistance and the long-term evolution of parasite populations in response to these control measures. Whereas we have some evidence for the role of specificity between host and pathogen genotypes in viral and bacterial infections, its role in macroparasitic infections is seldom considered. The first empirical test of this specificity for a vertebrate–nematode system is provided here using clonal lines of parasite and inbred and congenic strains of rat that differ either across the genome or only at the major histocompatibility complex. Although significant differences between the resistance of host genotypes to infection and between the fitness of different parasite genotypes are found, there is no evidence for an interaction between host and parasite genotypes. It is concluded that a specificity between host and parasite genotypes is unlikely in this system.     

A general model for the influence of immune priming on disease prevalence

Invertebrate immune priming, and other forms of innate immune memory in bacteria, plants, and mammals, modulate the post‐infection resistance, tolerance, and survival phenotypes of individuals previously exposed to microbes. By influencing the probability of both transmission and disease‐induced mortality, priming is likely to have a significant impact on disease dynamics. Two alternative models have been proposed as frameworks for the role of priming in infected populations, but the differences in their underlying key assumptions yield very different predictions for the effect of priming on disease dynamics. By examining these assumptions from the lens of within‐host dynamics, the model presented in this paper demonstrates that priming systems can be characterized along a continuous dose‐response gradient that unites these disparate frameworks. Moreover, it facilitates the incorporation of different kinds of immunological plasticity mechanisms, as well as the exposure probability and transmission characteristics of parasites. Simulating the interaction of these thresholds with the diversity of parasite life history strategies and distributions predicts that priming may actually inflate disease prevalence under certain conditions. Thus, priming of innate immune systems may act analogously to leaky vaccines and drive parasite virulence evolution. The results underscore the need for experimental studies that determine dose response curves for the both the probability of becoming primed following primary parasite exposure and shifts in resistance and tolerance in infected primed hosts. This framework is applicable to a variety of systems that show immunological memory.     

Host availability and the evolution of parasite life-history strategies

Parasites exploit an inherently patchy resource, their hosts, which are discrete entities that may only be available for infection within a relatively short time window. However, there has been little consideration of how heterogeneities in host availability may affect the phenotypic or genotypic composition of parasite populations or how parasites may evolve to cope with them. Here we conduct a selection experiment involving an entomopathogenic nematode (Steinernema feltiae) and show for the first time that the infection rate of a parasite can evolve rapidly to maximize the chances of infecting within an environment characterized by the rate of host availability. Furthermore, we show that the parasite's infection rate trades off with other fitness traits, such as fecundity and survival. Crucially, the outcome of competition between strains with different infection strategies depends on the rate of host availability; frequently available hosts favor "fast" infecting nematodes, whereas infrequently available hosts favor "slow" infecting nematodes. A simple evolutionarily stable strategy (ESS) analysis based on classic epidemiological models fails to capture this behavior, predicting instead that the fastest infecting phenotype should always dominate. However, a novel model incorporating more realistic, discrete bouts of host availability shows that strain coexistence is highly likely. Our results demonstrate that heterogeneities in host availability play a key role in the evolution of parasite life-history traits and in the maintenance of phenotypic variability. Parasite life-history strategies are likely to evolve rapidly in response to changes in host availability induced by disease management programs or by natural dynamics in host abundance. Incorporating parasite evolution in response to host availability would therefore enhance the predictive ability of current epidemiological models of infectious disease.     

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.     

Host life span and the evolution of resistance characteristics

There is a wide variety of resistance mechanisms that hosts may evolve in response to their parasites. These can be functionally classified as avoidance (lower probability of becoming infected), recovery (faster rate of clearance), tolerance (reduced death rate when infected), or acquired immunity. It is commonly thought that longer lived organisms should invest more in costly resistance. We show that due to epidemiological feedbacks the situation is often more complex. Using evolutionary theory we examine how the optimal investment in costly resistance varies with life span in a broad range of scenarios. In the absence of acquired immunity, longer lived populations do generally invest more in resistance. If hosts have acquired immunity, the optimal resistance may either increase or decrease with increasing life span. In addition, there may be evolutionary bistability with high and low investments in avoidance or tolerance. The optimal investment in the duration of acquired immunity always increases with life span, and due to bistability, shorter lived hosts may commonly not evolve any immunity. In contrast, the optimal investment in the probability of acquiring immunity initially increases and then decreases with life span. Our results have important implications for the evolution of invertebrate and vertebrate immunity, and for the evolution of acquired immunity itself.     

Long‐term selection experiment produces breakdown of horizontal transmissibility in parasite with mixed transmission mode

Evolutionary transitions from parasitism toward beneficial or mutualistic associations may encompass a change from horizontal transmission to (strict) vertical transmission. Parasites with both vertical and horizontal transmission are amendable to study factors driving such transitions. In a long‐term experiment, microcosm populations of the protozoan Paramecium caudatum and its bacterial parasite Holospora undulata were exposed to three growth treatments, manipulating vertical transmission opportunities over ca. 800 host generations. In inoculation tests, horizontal transmission propagules produced by parasites from a “high‐growth” treatment, with elevated host division rates increasing levels of parasite vertical transmission, showed a near‐complete loss of infectivity. A similar reduction was observed for parasites from a treatment alternating between high growth and low growth (i.e., low levels of population turn‐over). Parasites from a low‐growth treatment had the highest infectivity on all host genotypes tested. Our results complement previous findings of reduced investment in horizontal transmission and increased vertical transmissibility of high‐growth parasites. We explain the loss of horizontal transmissibility by epidemiological feedbacks and resistance evolution, reducing the frequency of susceptible hosts in the population and thereby decreasing the selective advantage of horizontal transmission. This illustrates how environmental conditions may push parasites with a mixed transmission mode toward becoming vertically transmitted nonvirulent symbionts.     

Parasite host range and the evolution of host resistance

Parasite host range plays a pivotal role in the evolution and ecology of hosts and the emergence of infectious disease. Although the factors that promote host range and the epidemiological consequences of variation in host range are relatively well characterized, the effect of parasite host range on host resistance evolution is less well understood. In this study, we tested the impact of parasite host range on host resistance evolution. To do so, we used the host bacterium Pseudomonas fluorescens SBW25 and a diverse suite of coevolved viral parasites (lytic bacteriophage Φ2) with variable host ranges (defined here as the number of host genotypes that can be infected) as our experimental model organisms. Our results show that resistance evolution to coevolved phages occurred at a much lower rate than to ancestral phage (approximately 50% vs. 100%), but the host range of coevolved phages did not influence the likelihood of resistance evolution. We also show that the host range of both single parasites and populations of parasites does not affect the breadth of the resulting resistance range in a naïve host but that hosts that evolve resistance to single parasites are more likely to resist other (genetically) more closely related parasites as a correlated response. These findings have important implications for our understanding of resistance evolution in natural populations of bacteria and viruses and other host–parasite combinations with similar underlying infection genetics, as well as the development of phage therapy.     

Rapid evolution and ecological host-parasite dynamics

Traditionally, the termination of parasite epidemics has been attributed to ecological causes: namely, the depletion of susceptible hosts as a result of mortality or acquired immunity. Here, we suggest that epidemics can also end because of rapid host evolution. Focusing on a particular host–parasite system, Daphnia dentifera and its parasite Metschnikowia bicuspidata , we show that Daphnia from lakes with recent epidemics were more resistant to infection and had less variance in susceptibility than Daphnia from lakes without recent epidemics. However, our studies revealed little evidence for genetic variation in infectivity or virulence in Metschnikowia . Incorporating the observed genetic variation in host susceptibility into an epidemiological model parameterized for this system reveals that rapid evolution can explain the termination of epidemics on time scales matching what occurs in lake populations. Thus, not only does our study provide rare evidence for parasite-mediated selection in natural populations, it also suggests that rapid evolution has important effects on short-term host–parasite dynamics.     

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.     

Host behaviour–parasite feedback: an essential link between animal behaviour and disease ecology

Animal behaviour and the ecology and evolution of parasites are inextricably linked. For this reason, animal behaviourists and disease ecologists have been interested in the intersection of their respective fields for decades. Despite this interest, most research at the behaviour–disease interface focuses either on how host behaviour affects parasites or how parasites affect behaviour, with little overlap between the two. Yet, the majority of interactions between hosts and parasites are probably reciprocal, such that host behaviour feeds back on parasites and vice versa. Explicitly considering these feedbacks is essential for understanding the complex connections between animal behaviour and parasite ecology and evolution. To illustrate this point, we discuss how host behaviour–parasite feedbacks might operate and explore the consequences of feedback for studies of animal behaviour and parasites. For example, ignoring the feedback of host social structure on parasite dynamics can limit the accuracy of predictions about parasite spread. Likewise, considering feedback in studies of parasites and animal personalities may provide unique insight about the maintenance of variation in personality types. Finally, applying the feedback concept to links between host behaviour and beneficial, rather than pathogenic, microbes may shed new light on transitions between mutualism and parasitism. More generally, accounting for host behaviour–parasite feedbacks can help identify critical gaps in our understanding of how key host behaviours and parasite traits evolve and are maintained.     

The evolution of resistance through costly acquired immunity

We examine the evolutionary dynamics of resistance to parasites through acquired immunity. Resistance can be achieved through the innate mechanisms of avoidance of infection and reduced pathogenicity once infected, through recovery from infection and through remaining immune to infection: acquired immunity. We assume that each of these mechanisms is costly to the host and find that the evolutionary dynamics of innate immunity in hosts that also have acquired immunity are quantitatively the same as in hosts that possess only innate immunity. However, compared with resistance through avoidance or recovery, there is less likely to be polymorphism in the length of acquired immunity within populations. Long-lived organisms that can recover at intermediate rates faced with fast-transmitting pathogens that cause intermediate pathogenicity (mortality of infected individuals) are most likely to evolve long-lived acquired immunity. Our work emphasizes that because whether or not acquired immunity is beneficial depends on the characteristics of the disease, organisms may be selected to only develop acquired immunity to some of the diseases that they encounter.     

Malaria parasites and red blood cells: from anaemia to transmission

Malaria parasites, Plasmodium spp., invade and exploit red blood cells during their asexual expansion within the vertebrate host. The parasite has evolved a suite of adaptive mechanisms enabling optimal exploitation of the host blood cell environment, avoiding host destruction, maintaining a parasite reservoir of infection and producing sexual transmission stages to infect mosquitoes. The highly variable nature of the host blood environment, both over the course of an infection and as a result of other parasitic infections, has selected for the evolution of considerable phenotypic plasticity in the parasite's response to its environment, particularly those phenotypes concerning transmission of the parasite to mosquitoes. With the evolution of human society, human malaria disease is becoming an increasingly urban problem. This imposes different selection pressures on the parasite. The extent to which the parasite is truly plastic over the short term rather than adaptive over the long term will determine the urban epidemiology of malaria and is essential for developing appropriate control methods. Understanding the adaptive nature of malaria parasites is thus vital for anticipating the future visage of urban human malaria.     

The evolution of parasites in response to tolerance in their hosts: the good, the bad, and apparent commensalism

Tolerance to parasites reduces the harm that infection causes the host (virulence). Here we investigate the evolution of parasites in response to host tolerance. We show that parasites may evolve either higher or lower within-host growth rates depending on the nature of the tolerance mechanism. If tolerance reduces virulence by a constant factor, the parasite is always selected to increase its growth rate. Alternatively, if tolerance reduces virulence in a nonlinear manner such that it is less effective at reducing the damage caused by higher growth rates, this may select for faster or slower replicating parasites. If the host is able to completely tolerate pathogen damage up to a certain replication rate, this may result in apparent commensalism, whereby infection causes no apparent virulence but the original evolution of tolerance has been costly. Tolerance tends to increase disease prevalence and may therefore lead to more, rather than less, disease-induced mortality. If the parasite is selected, even a highly efficient tolerance mechanism may result in more individuals in total dying from disease. However, the evolution of tolerance often, although not always, reduces the individual risk of dying from infection.