Autoimmunity and the microbiome: T‐cell receptor mimicry of “self” and microbial antigens mediates self tolerance in holobionts

I propose a T‐cell receptor (TcR)‐based mechanism by which immunity mediates both “genetic self” and “microbial self” thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross‐reactivity with “self,” resulting in selection for a TcR repertoire mimicking “genetic self.” Second, evolution has selected for a “microbial self” that mimics “genetic self” so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR‐microbiome mimicry “holoimmunity” to denote immune tolerance to the “holobiont self.” Logically, microbiome‐host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross‐react with host antigens producing “holoautoimmunity.”

     

Use of trade-off theory to advance understanding of herbivore–parasite interactions

• 1 Trade‐off theory has been extensively used to further our understanding of animal behaviour. In mammalian herbivores, it has been used to advance our understanding of their reproductive, parental care and foraging strategies. Here, we detail how trade‐off theory can be applied to herbivore–parasite interactions, especially in foraging environments.
• 2 Foraging is a common mode of uptake of parasites that represent the most pervasive challenge to mammalian fitness and survival. Hosts are hypothesized to alter their foraging behaviour in the presence of parasites in three ways: (i) hosts avoid foraging in areas that are contaminated with parasites; (ii) hosts select diets that increase their resistance and resilience to parasites; and (iii) hosts select for foods with direct anti‐parasitic properties (self‐medication). We concentrate on the mammalian herbivore literature to detail the recent advances made using trade‐off frameworks to understand the mechanisms behind host–parasite interactions in relation to these three hypotheses.
• 3 In natural systems, animals often face complex foraging decisions including nutrient intake vs. predation risk, nutrient intake vs. sheltering and nutrient intake vs. parasite risk trade‐offs. A trade‐off framework is detailed that can be used to interpret mammal behaviour in complex environments, and may be used to advance the self‐medication hypothesis.
• 4 The use of trade‐off theory has advanced our understanding of the contact process between grazing mammalian hosts and their parasites transmitted via the faecal–oral route. Experimental manipulation of the costs and benefits of a nutrient intake vs. parasite risk trade‐off has shown that environmental conditions (forage quality and quantity) and the physiological state (parasitic and immune status) of a mammalian host can both affect the behavioural decisions of foraging animals.
• 5 Naturally occurring trade‐offs and the potential to manipulate their costs and benefits enables us to identify the abilities and behavioural rules used by mammals when making decisions in complex environments and thus predict animal behaviour.

     

Egg mimicry by the Pacific koel: mimicry of one host facilitates exploitation of other hosts with similar egg types

When brood parasites exploit multiple host species, egg rejection by hosts may select for the evolution of host‐specific races, where each race mimics a particular host's egg type. However, some brood parasites that exploit multiple hosts with the ability to reject foreign eggs appear to have only a single egg type. In these cases, it is unclear how the parasite egg escapes detection by its hosts. Three possible explanations are: 1) host‐specific races are present, but differences in egg morphology are difficult for the human eye to detect; 2) the brood parasite evolves a single egg type that is intermediate in appearance between the eggs of its hosts; 3) or the parasite evolves mimicry of one of its hosts, which subsequently allows it to exploit other species with similar egg morphology. Here we test these possibilities by quantifying parameters of egg appearance of the brood‐parasitic Pacific koel Eudynamys orientalis and seven of its hosts. Koel eggs laid in the nests of different hosts did not show significant differences in colour or pattern, suggesting that koels have not evolved host‐specific races. Koel eggs were similar in colour, luminance and pattern to the majority of hosts, but were significantly more similar in colour and luminance to one of the major hosts than to two other major hosts, supporting hypothesis 3. Our findings suggest that mimicry of one host can allow a brood parasite to exploit new hosts with similar egg morphologies, which could inhibit the evolution of host defences in naïve hosts.     

Partitioning the influence of ecology across scales on parasite evolution

Vector‐borne parasites must succeed at three scales to persist: they must proliferate within a host, establish in vectors, and transmit back to hosts. Ecology outside the host undergoes dramatic seasonal and human‐induced changes, but predicting parasite evolutionary responses requires integrating their success across scales. We develop a novel, data‐driven model to titrate the evolutionary impact of ecology at multiple scales on human malaria parasites. We investigate how parasites invest in transmission versus proliferation, a life‐history trait that influences disease severity and spread. We find that transmission investment controls the pattern of host infectiousness over the course of infection: a trade‐off emerges between early and late infectiousness, and the optimal resolution of that trade‐off depends on ecology outside the host. An expanding epidemic favors rapid proliferation, and can overwhelm the evolutionary influence of host recovery rates and mosquito population dynamics. If transmission investment and recovery rate are positively correlated, then ecology outside the host imposes potent selection for aggressive parasite proliferation at the expense of transmission. Any association between transmission investment and recovery represents a key unknown, one that is likely to influence whether the evolutionary consequences of interventions are beneficial or costly for human health.     

HOST GROWTH CONDITIONS INFLUENCE EXPERIMENTAL EVOLUTION OF LIFE HISTORY AND VIRULENCE OF A PARASITE WITH VERTICAL AND HORIZONTAL TRANSMISSION

In parasites with mixed modes of transmission, ecological conditions may determine the relative importance of vertical and horizontal transmission for parasite fitness. This may lead to differential selection pressure on the efficiency of the two modes of transmission and on parasite virulence. In populations with high birth rates, increased opportunities for vertical transmission may select for higher vertical transmissibility and possibly lower virulence. We tested this idea in experimental populations of the protozoan Paramecium caudatum and its bacterial parasite Holospora undulata. Serial dilution produced constant host population growth and frequent vertical transmission. Consistent with predictions, evolved parasites from this “high‐growth” treatment had higher fidelity of vertical transmission and lower virulence than parasites from host populations constantly kept near their carrying capacity (“low‐growth treatment”). High‐growth parasites also produced fewer, but more infectious horizontal transmission stages, suggesting the compensation of trade‐offs between vertical and horizontal transmission components in this treatment. These results illustrate how environmentally driven changes in host demography can promote evolutionary divergence of parasite life history and transmission strategies.     

Host condition as a constraint for parasite reproduction

Environmental stress has been suggested to increase host susceptibility to infections and reduce host ability to resist parasite growth and reproduction, thus benefiting parasites. This prediction stems from expected costs of immune defence; hosts in poor condition should have less resources to be allocated to immune function. However, the alternative hypothesis for response to environmental stress is that hosts in poor condition provide less resources for parasites and/or suffer higher mortality, leading to reduced parasite growth, reproduction and survival. We contrasted these alternative hypotheses in a trematode–snail ( Diplostomum spathaceum – Lymnaea stagnalis ) system by asking: (1) how host condition affects parasite reproduction (amount and quality of produced transmission stages) and (2) how host condition affects the survival of infected host individuals. We experimentally manipulated host condition by starving the snails, and found that parasites produced fewer and poorer quality transmission stages in stressed hosts. Furthermore, starvation increased snail mortality. These findings indicate that in well-established trematode infections, reduced ability of immune allocation has no effect on host exploitation by parasites. Instead, deteriorating resources for the snail host can directly limit the amount of resources available for the parasite. This, together with increased host mortality, may have negative effects on parasite populations in the wild.     

Parasite diversity declines with host evolutionary distinctiveness: A global analysis of carnivores

Evolutionarily distinctive host lineages might harbor fewer parasite species because they have fewer opportunities for parasite sharing than hosts having extant close relatives, or because diverse parasite assemblages promote host diversification. We evaluate these hypotheses using data from 930 species of parasites reported to infect free‐living carnivores. We applied nonparametric richness estimators to estimate parasite diversity among well‐sampled carnivore species and assessed how well host evolutionary distinctiveness, relative to other biological and environmental factors, explained variation in estimated parasite diversity. Species richness estimates indicate that the current published literature captures less than 50% of the true parasite diversity for most carnivores. Parasite species richness declined with evolutionary distinctiveness of carnivore hosts (i.e., length of terminal ranches of the phylogeny) and increased with host species body mass and geographic range area. We found no support for the hypothesis that hosts from more diverse lineages support a higher number of generalist parasites, but we did find evidence that parasite assemblages might have driven host lineage diversification through mechanisms linked to sexual selection. Collectively, this work provides strong support for host evolutionary history being an essential predictor of parasite diversity, and offers a simple model for predicting parasite diversity in understudied carnivore species.     

Variation in costs of parasite resistance among natural host populations

Organisms that can resist parasitic infection often have lower fitness in the absence of parasites. These costs of resistance can mediate host evolution during parasite epidemics. For example, large epidemics will select for increased host resistance. In contrast, small epidemics (or no disease) can select for increased host susceptibility when costly resistance allows more susceptible hosts to outcompete their resistant counterparts. Despite their importance for evolution in host populations, costs of resistance (which are also known as resistance trade‐offs) have mainly been examined in laboratory‐based host–parasite systems. Very few examples come from field‐collected hosts. Furthermore, little is known about how resistance trade‐offs vary across natural populations. We addressed these gaps using the freshwater crustacean Daphnia dentifera and its natural yeast parasite, Metschnikowia bicuspidata. We found a cost of resistance in two of the five populations we studied – those with the most genetic variation in resistance and the smallest epidemics in the previous year. However, yeast epidemics in the current year did not alter slopes of these trade‐offs before and after epidemics. In contrast, the no‐cost populations showed little variation in resistance, possibly because large yeast epidemics eroded that variation in the previous year. Consequently, our results demonstrate variation in costs of resistance in wild host populations. This variation has important implications for host evolution during epidemics in nature.     

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.     

ON THE EVOLUTION OF SEXUAL REPRODUCTION IN HOSTS COEVOLVING WITH MULTIPLE PARASITES

Host–parasite coevolution has been studied extensively in the context of the evolution of sex. Although hosts typically coevolve with several parasites, most studies considered one‐host/one‐parasite interactions. Here, we study population‐genetic models in which hosts interact with two parasites. We find that host/multiple‐parasite models differ nontrivially from host/single‐parasite models. Selection for sex resulting from interactions with a single parasite is often outweighed by detrimental effects due to the interaction between parasites if coinfection affects the host more severely than expected based on single infections, and/or if double infections are more common than expected based on single infections. The resulting selection against sex is caused by strong linkage‐disequilibria of constant sign that arise between host loci interacting with different parasites. In contrast, if coinfection affects hosts less severely than expected and double infections are less common than expected, selection for sex due to interactions with individual parasites can now be reinforced by additional rapid linkage‐disequilibrium oscillations with changing sign. Thus, our findings indicate that the presence of an additional parasite can strongly affect the evolution of sex in ways that cannot be predicted from single‐parasite models, and that thus host/multiparasite models are an important extension of the Red Queen Hypothesis.     

Does investment into ��expensive�� tissue compromise anti-parasitic defence? Testes size, brain size and parasite diversity in rodent hosts

Species richness of parasite assemblages varies among host species. Earlier studies that searched for host-related determinants of parasite diversity mainly considered host traits that affect the probability of host encounter with parasites, whereas host traits related to defensibility against parasites have rarely been investigated. From the latter perspective, evolutionary investment in ??expensive?? tissue or organs (like testes or brain) may trade off against energetically costly anti-parasitic defences. If so, richer parasite assemblages are expected in hosts with larger testes and brains. We studied the relationships between testes and brain size and diversity of parasites (fleas, gamasid mites and helminths) in 55 rodent species using a comparative approach and application of two methods, namely the method of independent contrasts and generalized least-squares (GLS) analysis. Both phylogenetically correct methods produced similar results for flea and helminth species richness. Testes size positively correlated with flea and helminth species richness but not gamasid mite species richness. No correlation between brain size and species richness of any parasite group was found by the method of independent contrasts. However, GLS analysis indicated negative correlation between brain size and mite species richness. Our results cast doubt on the validity of the expensive tissue hypothesis, but suggest instead that larger testes are associated with higher parasite diversity via their effect on mobility and/or testosterone-mediated immunosuppression.     

Imperfect mimicry of host begging calls by a brood parasitic cuckoo: a cue for nestling rejection by hosts?

Coevolutionary interactions between avian brood parasites and their hosts often lead to the evolution of discrimination and rejection of parasite eggs or chicks by hosts based on visual cues, and the evolution of visual mimicry of host eggs or chicks by brood parasites. Hosts may also base rejection of brood parasite nestlings on vocal cues, which would in turn select for mimicry of host begging calls in brood parasite chicks. In cuckoos that exploit multiple hosts with different begging calls, call structure may be plastic, allowing nestlings to modify their calls to match those of their various hosts, or fixed, in which case we would predict either imperfect mimicry or divergence of the species into host-specific lineages. In our study of the little bronze-cuckoo (LBC) Chalcites minutillus and its primary host, the large-billed gerygone Gerygone magnirostris, we tested whether: (1) hosts use nestling vocalizations as a cue to discriminate cuckoo chicks; (2) cuckoo nestlings mimic the host begging calls throughout the nestling period; and (3) the cuckoo begging calls are plastic, thereby facilitating mimicry of the calls of different hosts. We found that the begging calls of LBCs are most similar to their gerygone hosts shortly after hatching (when rejection by hosts typically occurs) but become less similar as cuckoo chicks get older. Begging call structure may be used as a cue for rejection by hosts, and these results are consistent with gerygone defenses selecting for age-specific vocal mimicry in cuckoo chicks. We found no evidence that LBC begging calls were plastic.     

Mimicry vs. similarity: which resemblances between brood parasites and their hosts are mimetic and which are not?

Mimicry is one of the most conspicuous and puzzling phenomena in nature. The best-known examples come from insects and brood parasitic birds. Unfortunately, the term 'mimicry' is used indiscriminately and inconsistently in the brood parasitic literature despite the obvious fact that similarities of eggs, nestlings and adults of brood parasites to their hosts could result from many different processes (phylogenetic constraint, predation, intraspecific arms-races, vocal imitation, exploitation of pre-existing preferences, etc.). In this note I wish to plead for a more careful use of the term. I review various processes leading to a similarity between propagules (both eggs and nestlings) of brood parasites and their hosts and stress that: (1) mimetic and non-mimetic similarities should be differentiated, (2) a mere similarity of host and parasite propagules provides no evidence for mimicry, (3) mimicry is more usefully understood as a (coevolutionary) process rather than an appearance, and (4) mimicry terminology should reflect the process which led to mimetic similarity. Accepting the mimicry hypothesis requires both the experimental approach and rejection of alternative hypotheses explaining similarities of host and parasite propagules.  © 2005 The Linnean Society of London, Biological Journal of the Linnean Society , 2005, 84 , 69–78.     

The cost of phage resistance in a plant pathogenic bacterium is context‐dependent

Parasites are ubiquitous features of living systems and many parasites severely reduce the fecundity or longevity of their hosts. This parasite‐imposed selection on host populations should strongly favor the evolution of host resistance, but hosts typically face a trade‐off between investment in reproductive fitness and investment in defense against parasites. The magnitude of such a trade‐off is likely to be context‐dependent, and accordingly costs that are key in shaping evolution in nature may not be easily observable in an artificial environment. We set out to assess the costs of phage resistance for a plant pathogenic bacterium in its natural plant host versus in a nutrient‐rich, artificial medium. We demonstrate that mutants of Pseudomonas syringae that have evolved resistance via a single mutational step pay a substantial cost for this resistance when grown on their tomato plant hosts, but do not realize any measurable growth rate costs in nutrient‐rich media. This work demonstrates that resistance to phage can significantly alter bacterial growth within plant hosts, and therefore that phage‐mediated selection in nature is likely to be an important component of bacterial pathogenicity.     

THE COEVOLUTIONARY IMPLICATIONS OF HOST TOLERANCE

Host tolerance to infectious disease, whereby hosts do not directly “fight” parasites but instead ameliorate the damage caused, is an important defense mechanism in both plants and animals. Because tolerance to parasite virulence may lead to higher prevalence of disease in a population, evolutionary theory tells us that while the spread of resistance genes will result in negative frequency dependence and the potential for diversification, the evolution of tolerance is instead likely to result in fixation. However, our understanding of the broader implications of tolerance is limited by a lack of fully coevolutionary theory. Here we examine the coevolution of tolerance across a comprehensive range of classic coevolutionary host–parasite frameworks, including equivalents of gene‐for‐gene and matching allele and evolutionary invasion models. Our models show that the coevolution of host tolerance and parasite virulence does not lead to the generation and maintenance of diversity through either static polymorphisms or through “Red‐queen” cycles. Coevolution of tolerance may however lead to multiple stable states leading to sudden shifts in parasite impacts on host health. More broadly, we emphasize that tolerance may change host–parasite interactions from antagonistic to a form of “apparent commensalism,” but may also lead to the evolution of parasites that are highly virulent in nontolerant hosts.     

The Ratchet and the Red Queen: the maintenance of sex in parasites

The adaptive significance of sexual reproduction remains as an unsolved problem in evolutionary biology. One promising hypothesis is that frequency‐dependent selection by parasites selects for sexual reproduction in hosts, but it is unclear whether such selection on hosts would feed back to select for sexual reproduction in parasites. Here we used individual‐based computer simulations to explore this possibility. Specifically, we tracked the dynamics of asexual parasites following their introduction into sexual parasite populations for different combinations of parasite virulence and transmission. Our results suggest that coevolutionary interactions with hosts would generally lead to a stable coexistence between sexual parasites and a single parasite clone. However, if multiple mutations to asexual reproduction were allowed, we found that the interaction led to the accumulation of clonal diversity in the asexual parasite population, which led to the eventual extinction of the sexual parasites. Thus, coevolution with sexual hosts may not be generally sufficient to select for sex in parasites. We then allowed for the stochastic accumulation of mutations in the finite parasite populations (Muller's Ratchet). We found that, for higher levels of parasite virulence and transmission, the population bottlenecks resulting from host–parasite coevolution led to the rapid accumulation of mutations in the clonal parasites and their elimination from the population. This result may explain the observation that sexual reproduction is more common in parasitic animals than in their free‐living relatives.     

Of mice and worms: are co-infections with unrelated parasite strains more damaging to definitive hosts?

Intraspecific competition between co-infecting parasites can influence the amount of virulence, or damage, they do to their host. Kin selection theory dictates that infections with related parasite individuals should have lower virulence than infections with unrelated individuals, because they benefit from inclusive fitness and increased host longevity. These predictions have been tested in a variety of microparasite systems, and in larval stage macroparasites within intermediate hosts, but the influence of adult macroparasite relatedness on virulence has not been investigated in definitive hosts. This study used the human parasite Schistosoma mansoni to determine whether definitive hosts infected with related parasites experience lower virulence than hosts infected with unrelated parasites, and to compare the results from intermediate host studies in this system. The presence of unrelated parasites in an infection decreased parasite infectivity, the ability of a parasite to infect a definitive host, and total worm establishment in hosts, impacting the less virulent parasite strain more severely. Unrelated parasite co-infections had similar virulence to the more virulent of the two parasite strains. We combine these findings with complementary studies of the intermediate snail host and describe trade-offs in virulence and selection within the life cycle. Damage to the host by the dominant strain was muted by the presence of a competitor in the intermediate host, but was largely unaffected in the definitive host. Our results in this host–parasite system suggest that unrelated infections may select for higher virulence in definitive hosts while selecting for lower virulence in intermediate hosts.     

A meta‐analysis of ant social parasitism: host characteristics of different parasitism types and a test of Emery’s rule

Abstract 1. In ant social parasitism, the process by which parasite–host systems evolved and the types of invasion mechanisms parasites use are being debated. Emery’s rule, for example, states that social parasites are the closest relatives to their hosts. The present study uses previously published data to test whether Emery’s rule applies equally to all parasitism types (i.e. xenobiosis, temporary, dulosis, and inquilinism). In addition, this study also investigates other links between parasite–host relatedness and host biology, which has implications for understanding the invasion mechanisms used by certain parasites. 2. We find that xenobiotic parasites typically use distantly‐related host species that are of at least medium colony size. Temporary parasites often have multiple host species that are very closely related to the parasite and hosts with medium‐size colonies. Dulotic parasites frequently have multiple host species that are slightly less related and of any size. Lastly, inquiline parasites tend to have a single, very closely related, host species with medium‐size colonies. 3. Parasites tend to be more closely related to host species if they have a single host species or when the host has a large colony size. In contrast, parasites with multiple host species or hosts of small colony size tend to be less related to their hosts. 4. This study is the first to examine trends in ant social parasitism across all known parasite species. Our meta‐analysis shows that Emery’s rule applies to inquilinism and temporary parasitism, but not to dulosis and xenobiosis. Our results also suggest that both parasitism type and parasite–host relatedness predict the number of hosts and host colony size. It may be that a chemical mimicry mechanism allows invasion of large host colonies, but requires close relatedness of parasite and host, and concentration on a single host species.     

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.