Enemies make you stronger: Coevolution between fruit fly host and bacterial pathogen increases postinfection survivorship in the host

Multiple laboratory studies have evolved hosts against a nonevolving pathogen to address questions about evolution of immune responses. However, an ecologically more relevant scenario is one where hosts and pathogens can coevolve. Such coevolution between the antagonists, depending on the mutual selection pressure and additive variance in the respective populations, can potentially lead to a different pattern of evolution in the hosts compared to a situation where the host evolves against a nonevolving pathogen. In the present study, we used Drosophila melanogaster as the host and Pseudomonas entomophila as the pathogen. We let the host populations either evolve against a nonevolving pathogen or coevolve with the same pathogen. We found that the coevolving hosts on average evolved higher survivorship against the coevolving pathogen and ancestral (nonevolving) pathogen relative to the hosts evolving against a nonevolving pathogen. The coevolving pathogens evolved greater ability to induce host mortality even in nonlocal (novel) hosts compared to infection by an ancestral (nonevolving) pathogen. Thus, our results clearly show that the evolved traits in the host and the pathogen under coevolution can be different from one‐sided adaptation. In addition, our results also show that the coevolving host–pathogen interactions can involve certain general mechanisms in the pathogen, leading to increased mortality induction in nonlocal or novel hosts.     

Evolution of pathogen virulence: the role of variation in host phenotype

Selection on pathogens tends to favour the evolution of growth and reproductive rates and a concomitant level of virulence (damage done to the host) that maximizes pathogen fitness. Yet, because hosts often pose varying selective environments to pathogens, one level of virulence may not be appropriate for all host types. Indeed, if a level of virulence confers high fitness to the pathogen in one host phenotype but low fitness in another host phenotype, alternative virulence strategies may be maintained in the pathogen population. Such strategies can occur either as polymorphism, where different strains of pathogen evolve specialized virulence strategies in different host phenotypes or as polyphenism, where pathogens facultatively express alternative virulence strategies depending on host phenotype. Polymorphism potentially leads to specialist pathogens capable of infecting a limited range of host phenotypes, whereas polyphenism potentially leads to generalist pathogens capable of infecting a wider range of hosts. Evaluating how variation among hosts affects virulence evolution can provide insight into pathogen diversity and is critical in determining how host pathogen interactions affect the phenotypic evolution of both hosts and pathogens.     

Population Processes at Multiple Spatial Scales Maintain Diversity and Adaptation in the Linum marginale - Melampsora lini Association

Host-pathogen coevolution is a major driver of species diversity, with an essential role in the generation and maintenance of genetic variation in host resistance and pathogen infectivity. Little is known about how resistance and infectivity are structured across multiple geographic scales and what eco-evolutionary processes drive these patterns. Across southern Australia, the wild flax Linum marginale is frequently attacked by its rust fungus Melampsora lini. Here, we compare the genetic and phenotypic structure of resistance and infectivity among population pairs from two regions where environmental differences associate with specific life histories and mating systems. We find that both host and pathogen populations are genetically distinct between these regions. The region with outcrossing hosts and pathogens that go through asexual cycles followed by sexual reproduction showed greater diversity of resistance and infectivity phenotypes, higher levels of resistance and less clumped within-population spatial distribution of resistance. However, in the region where asexual pathogens infect selfing hosts, pathogens were more infective and better adapted to sympatric hosts. Our findings largely agree with expectations based on the distinctly different host mating systems in the two regions, with a likely advantage for hosts undergoing recombination. For the pathogen in this system, sexual reproduction may primarily be a survival mechanism in the region where it is observed. While it appears to potentially have adverse effects on local adaptation in the short term, it may be necessary for longer-term coevolution with outcrossing hosts.     

Patterns of virulence and benevolence in insect‐borne pathogens of plants

Direct and indirect interactions between insect‐borne pathogens and their host plants are reviewed in the context of theoretical analyses of the evolution of virulence. Unlike earlier theories, which maintained that parasites should evolve to be harmless or even beneficial to their hosts, recent models predict that coevolution between pathogen and host may lead to virulence or avirulence, depending on the pathogen transmission system. The studies reviewed here support the hypothesis that virulence can be advantageous for insect‐borne pathogens of plants. Virulent pathogens may be transmitted more readily by vector insects and are likely to induce stronger disease symptoms, thereby potentially making the plant more attractive to vectors. In contrast, the transmission advantage of virulence for seed‐transmitted pathogens is lower and the costs of virulence are high. Pathogens may sometimes benefit plants via indirect interactions that arise through relationships with other organisms. Evidence for the effects of insect‐borne pathogens on plant competition, herbivory, and parasitism also is reviewed, but few studies have measured the outcome of both direct and indirect interactions. Benefits of pathogen infection that accrue to plants from indirect interactions may sometimes outweigh the direct detrimental effects of virulence.     

Relative number of generations of hosts and parasites does not influence parasite local adaptation in coevolving populations of bacteria and phages

A potential consequence of host-parasite coevolution in spatially structured populations is parasite local adaptation: local parasites perform better than foreign parasites on their local host populations. It has been suggested that the generally shorter generation times of parasites compared with their hosts contributes to parasites, rather than hosts, being locally adapted. We tested the hypothesis that relative generation times of hosts and parasites affect local adaptation of hosts and parasites, using the bacterium Pseudomonas fluorescens and a lytic phage as host and parasite, respectively. Generation times were not directly manipulated, but instead one of the coevolving partners was regularly removed and replaced with a population from an earlier time point. Thus, one partner underwent more generations than the other. Manipulations were carried out at both early and later periods of coevolutionary interactions. At early stages of coevolution, host and parasites that underwent relatively more generations displayed higher levels of resistance and infectivity, respectively. However, the relative number of generations that bacteria and phages underwent did not change the level of local adaptation relative to control populations. This is likely because generalist hosts and parasites are favoured during early stages of coevolution, preventing local adaptation. By contrast, at later stages manipulations had no effect on either average levels of resistance or infectivity, or alter the level of local adaptation relative to the controls, possibly because traits other than resistance and infectivity were under strong selection. Taken together, these data suggest that the relative generation times of hosts and parasites may not be an important determinant of local adaptation in this system.     

Host genotype and genetic diversity shape the evolution of a novel bacterial infection

Pathogens continue to emerge from increased contact with novel host species. Whilst these hosts can represent distinct environments for pathogens, the impacts of host genetic background on how a pathogen evolves post-emergence are unclear. In a novel interaction, we experimentally evolved a pathogen (Staphylococcus aureus) in populations of wild nematodes (Caenorhabditis elegans) to test whether host genotype and genetic diversity affect pathogen evolution. After ten rounds of selection, we found that pathogen virulence evolved to vary across host genotypes, with differences in host metal ion acquisition detected as a possible driver of increased host exploitation. Diverse host populations selected for the highest levels of pathogen virulence, but infectivity was constrained, unlike in host monocultures. We hypothesise that population heterogeneity might pool together individuals that contribute disproportionately to the spread of infection or to enhanced virulence. The genomes of evolved populations were sequenced, and it was revealed that pathogens selected in distantly-related host genotypes diverged more than those in closely-related host genotypes. S. aureus nevertheless maintained a broad host range. Our study provides unique empirical insight into the evolutionary dynamics that could occur in other novel infections of wildlife and humans.Subject terms: Molecular evolution, Bacterial evolution, Bacterial genetics     

Experimental manipulation of population‐level MHC diversity controls pathogen virulence evolution in Mus musculus

The virulence levels attained by serial passage of pathogens through similar host genotypes are much higher than observed in natural systems; however, it is unknown what keeps natural virulence levels below these empirically demonstrated maximum levels. One hypothesis suggests that host diversity impedes pathogen virulence, because adaptation to one host genotype carries trade‐offs in the ability to replicate and cause disease in other host genotypes. To test this hypothesis, with the simplest level of population diversity within the loci of the major histocompatibility complex (MHC), we serially passaged Friend virus complex (FVC) through two rounds, in hosts with either the same MHC genotypes (pure passage) or hosts with different MHC genotypes (alternated passage). Alternated passages showed a significant overall reduction in viral titre (31%) and virulence (54%) when compared to pure passages. Furthermore, a resistant host genotype initially dominated any effects due to MHC diversity; however, when FVC was allowed to adapt to the resistant host genotype, predicted MHC effects emerged; that is, alternated lines show reduced virulence. These data indicate serial exposure to diverse MHC genotypes is an impediment to pathogen adaptation, suggesting genetic variation at MHC loci is important for limiting virulence in a rapidly evolving pathogen and supports negative frequency‐dependent selection as a force maintaining MHC diversity in host populations.     

Host–Pathogen Coevolution: The Selective Advantage of Bacillus thuringiensis Virulence and Its Cry Toxin Genes

Reciprocal coevolution between host and pathogen is widely seen as a major driver of evolution and biological innovation. Yet, to date, the underlying genetic mechanisms and associated trait functions that are unique to rapid coevolutionary change are generally unknown. We here combined experimental evolution of the bacterial biocontrol agent Bacillus thuringiensis and its nematode host Caenorhabditis elegans with large-scale phenotyping, whole genome analysis, and functional genetics to demonstrate the selective benefit of pathogen virulence and the underlying toxin genes during the adaptation process. We show that: (i) high virulence was specifically favoured during pathogen–host coevolution rather than pathogen one-sided adaptation to a nonchanging host or to an environment without host; (ii) the pathogen genotype BT-679 with known nematocidal toxin genes and high virulence specifically swept to fixation in all of the independent replicate populations under coevolution but only some under one-sided adaptation; (iii) high virulence in the BT-679-dominated populations correlated with elevated copy numbers of the plasmid containing the nematocidal toxin genes; (iv) loss of virulence in a toxin-plasmid lacking BT-679 isolate was reconstituted by genetic reintroduction or external addition of the toxins. We conclude that sustained coevolution is distinct from unidirectional selection in shaping the pathogen''s genome and life history characteristics. To our knowledge, this study is the first to characterize the pathogen genes involved in coevolutionary adaptation in an animal host–pathogen interaction system.     

Pathogen and host genotype differently affect pathogen fitness through their effects on different life-history stages

ABSTRACT: BACKGROUND: Adaptation of pathogens to their hosts depends critically on factorsaffecting pathogen reproductive rate. While pathogen reproduction is the end result of an intricate interaction between host and pathogen, the relative contributions of host and pathogen genotype to variation in pathogen life history within the hostare not well understood. Untangling these contributions allows us to identify traits withsufficient genetic variation for selection to act and to identify mechanisms of coevolution between pathogens and their hosts. We investigated the effects of pathogen and host genotype on three life-history components of pathogen fitness; infection efficiency, latent period, and sporulation capacity, in the oat crown rust fungus, Puccinia coronata f.sp. avenae, as it infects oats (Avena sativa). RESULTS: We show that both pathogen and host genotype significantly affect total spore production butdo so through their effects on different life-history stages. Pathogen genotype has the strongest effect on the early stage of infection efficiency, while host genotype most strongly affects the later life-history stages of latent period and sporulation capacity.In addition, host genotype affected the relationship between pathogen density and the later life-history traits oflatent period and sporulation capacity. We did not find evidence of pathogen-by-host genotypic (GxG) interactions. CONCLUSION: Our results illustrate mechanisms by which variation in host populationswill affect the evolution of pathogen lifehistory. Results show that differentpathogen life-history stages have the potential to respond differently to selection by host or pathogen genotypeand suggest mechanisms of antagonistic coevolution. Pathogen populations may adapt tohost genotype through increased infection efficiency while their plant hosts may adapt by limiting the later stages ofpathogen growthand spore production within the host.     

Local biotic environment shapes the spatial scale of bacteriophage adaptation to bacteria

The ecological, epidemiological, and evolutionary consequences of host-parasite interactions are critically shaped by the spatial scale at which parasites adapt to hosts. The scale of interaction between hyperparasites and their parasites is likely to be influenced by the host of the parasite and potentially likely to differ among within-host environments. Here we examine the scale at which bacteriophages adapt to their host bacteria by studying natural isolates from the surface or interior of horse chestnut leaves. We find that phages are more infective to bacteria from the same tree relative to those from other trees but do not differ in infectivity to bacteria from different leaves within the same tree. The results suggest that phages target common bacterial species, including an important plant pathogen, within plant host tissues; this result has important implications for therapeutic phage epidemiology. Furthermore, we show that phages from the leaf interior are more infective to their local hosts than phages from the leaf surface are to theirs, suggesting either increased resistance of bacteria on the leaf surface or increased phage adaptation within the leaf. These results highlight that biotic environment can play a key role in shaping the spatial scale of parasite adaptation and influencing the outcome of coevolutionary interactions.     

MHC polymorphism under host-pathogen coevolution

The genes encoding major histocompatibility (MHC) molecules are among the most polymorphic genes known for vertebrates. Since MHC molecules play an important role in the induction of immune responses, the evolution of MHC polymorphism is often explained in terms of increased protection of hosts against pathogens. Two selective pressures that are thought to be involved are (1) selection favoring MHC heterozygous hosts, and (2) selection for rare MHC alleles by host-pathogen coevolution. We have developed a computer simulation of coevolving hosts and pathogens to study the relative impact of these two mechanisms on the evolution of MHC polymorphism. We found that heterozygote advantage per se is insufficient to explain the high degree of polymorphism at the MHC, even in very large host populations. Host-pathogen coevolution, on the other hand, can easily account for realistic polymorphisms of more than 50 alleles per MHC locus. Since evolving pathogens mainly evade presentation by the most common MHC alleles in the host population, they provide a selective pressure for a large variety of rare MHC alleles. Provided that the host population is sufficiently large, a large set of MHC alleles can persist over many host generations under host-pathogen coevolution, despite the fact that allele frequencies continuously change.Electronic Supplementary Material Supplementary material is available in the online version of this article at     

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.     

Coevolutionary cycling of host sociality and pathogen virulence in contact networks

Infectious diseases may place strong selection on the social organization of animals. Conversely, the structure of social systems can influence the evolutionary trajectories of pathogens. While much attention has focused on the evolution of host sociality or pathogen virulence separately, few studies have looked at their coevolution. Here we use an agent-based simulation to explore host-pathogen coevolution in social contact networks. Our results indicate that under certain conditions, both host sociality and pathogen virulence exhibit continuous cycling. The way pathogens move through the network (e.g., their interhost transmission and probability of superinfection) and the structure of the network can influence the existence and form of cycling.     

Coevolutionary genetics of plants and pathogens

Summary The genetic polymorphism maintained by host-pathogen coevolution is analysed in a multilocus model. The model assumes gene-for-gene interactions of the type commonly observed between host plants and their fungal pathogens. Unstable (epidemic) systems maintain more resistance genes, fewer virulence genes, and less overall genetic diversity than stable (endemic) diseases. The stability of the system depends primarily on demographic parameters, such as the pathogen's intrinsic rate of increase, rather than genetic parameters, such as the costs of resistance and virulence. At equilibrium the model predicts that the number of resistance alleles in each host plant follows a binomial distribution that depends on the cost to the pathogen for carrying virulence alleles. Similarly, the number of virulence alleles in each pathogen spore follows a binomial distribution that depends on one minus the cost to the host for carrying resistance alleles. Data from wild populations match the predicted binomial distributions.     

Imperfect vaccines and the evolution of pathogens causing acute infections in vertebrates

A study by Gandon et al. (2001) considered the potential ways pathogens may evolve in response to vaccination with imperfect vaccines. In this paper, by focusing on acute infections of vertebrate hosts, we examine whether imperfect vaccines that do not completely block a pathogen's replication (antigrowth) or transmission (antitransmission) may lead to evolution of more or less virulent pathogen strains. To address this question, we use models of the within-host dynamics of the pathogen and the host's immune responses. One advantage of the use of this within-host approach is that vaccination can be easily incorporated in the models and the trade-offs between pathogen transmissibility, host recovery, and virulence that drive evolution of pathogens in these models can be easily estimated. We find that the use of either antigrowth or antitransmission vaccines leads to the evolution of pathogens with an increased within-host growth rate; infection of unvaccinated hosts with such evolved pathogens results in high host mortality and low pathogen transmission. Vaccination of only a fraction of hosts with antigrowth vaccines may prevent pathogens from evolving high virulence due to pathogen adaptation to unvaccinated hosts and thus protection of vaccinated hosts from pathogen-induced disease. In contrast, antitransmission vaccines may be beneficial only if they are effective enough to cause pathogen extinction. Our results suggest that particular mechanisms of action of vaccines and their efficacy are crucial in predicting longterm evolutionary consequences of the use of imperfect vaccines.     

Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence

Pathogens that can be transmitted between different host species are of fundamental interest and importance from public health, conservation and economic perspectives, yet systematic quantification of these pathogens is lacking. Here, pathogen characteristics, host range and risk factors determining disease emergence were analysed by constructing a database of disease-causing pathogens of humans and domestic mammals. The database consisted of 1415 pathogens causing disease in humans, 616 in livestock and 374 in domestic carnivores. Multihost pathogens were very prevalent among human pathogens (61.6%) and even more so among domestic mammal pathogens (livestock 77.3%, carnivores 90.0%). Pathogens able to infect human, domestic and wildlife hosts contained a similar proportion of disease-causing pathogens for all three host groups. One hundred and ninety-six pathogens were associated with emerging diseases, 175 in humans, 29 in livestock and 12 in domestic carnivores. Across all these groups, helminths and fungi were relatively unlikely to emerge whereas viruses, particularly RNA viruses, were highly likely to emerge. The ability of a pathogen to infect multiple hosts, particularly hosts in other taxonomic orders or wildlife, were also risk factors for emergence in human and livestock pathogens. There is clearly a need to understand the dynamics of infectious diseases in complex multihost communities in order to mitigate disease threats to public health, livestock economies and wildlife.     

THE JACK OF ALL TRADES IS MASTER OF NONE: A PATHOGEN'S ABILITY TO INFECT A GREATER NUMBER OF HOST GENOTYPES COMES AT A COST OF DELAYED REPRODUCTION

A trade‐off between a pathogen's ability to infect many hosts and its reproductive capacity on each host genotype is predicted to limit the evolution of an expanded host range, yet few empirical results provide evidence for the magnitude of such trade‐offs. Here, we test the hypothesis for a trade‐off between the number of host genotypes that a fungal pathogen can infect (host genotype range) and its reproductive capacity on susceptible plant hosts. We used strains of the oat crown rust fungus that carried widely varying numbers of virulence (avr) alleles known to determine host genotype range. We quantified total spore production and the expression of four pathogen life‐history stages: infection efficiency, time until reproduction, pustule size, and spore production per pustule. In support of the trade‐off hypothesis, we found that virulence level, the number of avr alleles per pathogen strain, was correlated with significant delays in the onset of reproduction and with smaller pustule sizes. Modeling from our results, we conclude that trade‐offs have the capacity to constrain the evolution of host genotype range in local populations. In contrast, long‐term trends in virulence level suggest that the continued deployment of resistant host lines over wide regions of the United States has generated selection for increased host genotype range.     

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.     

Host-parasite local adaptation after experimental coevolution of Caenorhabditis elegans and its microparasite Bacillus thuringiensis

Coevolving hosts and parasites can adapt to their local antagonist. In studies on natural populations, the observation of local adaptation patterns is thus often taken as indirect evidence for coevolution. Based on this approach, coevolution was previously inferred from an overall pattern of either parasite or host local adaptation. Many studies, however, failed to detect such a pattern. One explanation is that the studied system was not subject to coevolution. Alternatively, coevolution occurred, but remained undetected because it took different routes in different populations. In some populations, it is the host that is locally adapted, whereas in others it is the parasite, leading to the absence of an overall local adaptation pattern. Here, we test for overall as well as population-specific patterns of local adaptation using experimentally coevolved populations of the nematode Caenorhabditis elegans and its bacterial microparasite Bacillus thuringiensis. Furthermore, we assessed the importance of random interaction effects using control populations that evolved in the absence of the respective antagonist. Our results demonstrate that experimental coevolution produces distinct local adaptation patterns in different replicate populations, including host, parasite or absence of local adaptation. Our study thus provides experimental evidence of the predictions of the geographical mosaic theory of coevolution, i.e. that the interaction between parasite and host varies across populations.     

LOCAL MALADAPTATION IN THE ANTHER-SMUT FUNGUS MICROBOTRYUM VIOLACEUM TO ITS HOST PLANT SILENE LATIFOLIA: EVIDENCE FROM A CROSS-INOCULATION EXPERIMENT

Conventional wisdom holds that parasites evolve more rapidly than their hosts and are therefore locally adapted, that is, better at exploiting sympatric than allopatric hosts. We studied local adaptation in the insect-transmitted fungal pathogen Microbotryum violaceum and its host plant Silene latifolia. Infection success was tested in sympatric (local) and allopatric (foreign) combinations of pathogen and host from 14 natural populations from a metapopulation. Seedlings from up to 10 seed families from each population were exposed to sporidial suspensions from each of four fungal strains derived from the same population, from a near-by population (< 10 km distance), and from two populations at an intermediate (< 30 km) and remote (< 170 km) distance, respectively. We obtained significant pathogen X plant interactions in infection success (proportion of diseased plants) at both fungal population and strain level. There was an overall pattern of local maladaptation of this pathogen: average fungal infection success was significantly lower on sympatric hosts (mean proportion of diseased plants = 0.32 ± 0.03 SE) than on allopatric hosts (0.40 ± 0.02). Five of the 14 fungal populations showed no strong reduction in infection success on sympatric hosts, and three even tended to perform better on sympatric hosts. This pattern is consistent with models of time-lagged cycles predicting patterns of local adaptation in host-parasite systems to emerge only on average. Several factors may restrict the evolutionary potential of this pathogen relative to that of its host. First, a predominantly selfing breeding system may limit its ability to generate new virulence types by sexual recombination, whereas the obligately outcrossing host 5. latifolia may profit from rearrangement of resistance alleles by random mating. Second, populations often harbor only a few infected individuals, so virulence variation may be further reduced by drift. Third, migration rates among host plant populations are much higher than among pathogen populations, possibly because pollinators prefer healthy over diseased plants. Migration among partly isolated populations may therefore introduce novel host plant resistance variants more often than novel parasite virulence variants. That migration contributes to the coevolutionary dynamics in this system is supported by the geographic pattern of infectivity. Infection success increased over the first 10–km range of host-pathogen population distances, which is likely the natural range of gene exchange.