Within-host parasite cooperation and the evolution of virulence

Infections by multiple genotypes are common in nature and are known to select for higher levels of virulence for some parasites. When parasites produce public goods (PGs) within the host, such co-infections have been predicted to select for lower levels of virulence. However, this prediction is based on simplifying assumptions regarding epidemiological feedbacks on the multiplicity of infections (MOI). Here, we analyse the case of parasites producing a PG (for example, siderophore-producing bacteria) using a nested model that ties together within-host and epidemiological processes. We find that the prediction that co-infection should select for less virulent strains for PG-producing parasites is only valid if both parasite transmission and virulence are linear functions of parasite density. If there is a trade-off relationship such that virulence increases more rapidly than transmission, or if virulence also depends on the total amount of PGs produced, then more complex relationships between virulence and the MOI are predicted. Our results reveal that explicitly taking into account the distribution of parasite strains among hosts could help better understand the selective pressures faced by parasites at the population level.     

The virulence–transmission trade-off in vector-borne plant viruses: a review of (non-)existing studies

The adaptive hypothesis invoked to explain why parasites harm their hosts is known as the trade-off hypothesis, which states that increased parasite transmission comes at the cost of shorter infection duration. This correlation arises because both transmission and disease-induced mortality (i.e. virulence) are increasing functions of parasite within-host density. There is, however, a glaring lack of empirical data to support this hypothesis. Here, we review empirical investigations reporting to what extent within-host viral accumulation determines the transmission rate and the virulence of vector-borne plant viruses. Studies suggest that the correlation between within-plant viral accumulation and transmission rate of natural isolates is positive. Unfortunately, results on the correlation between viral accumulation and virulence are very scarce. We found only very few appropriate studies testing such a correlation, themselves limited by the fact that they use symptoms as a proxy for virulence and are based on very few viral genotypes. Overall, the available evidence does not allow us to confirm or refute the existence of a transmission–virulence trade-off for vector-borne plant viruses. We discuss the type of data that should be collected and how theoretical models can help us refine testable predictions of virulence evolution.     

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

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

Empirical support for optimal virulence in a castrating parasite

The trade-off hypothesis for the evolution of virulence predicts that parasite transmission stage production and host exploitation are balanced such that lifetime transmission success (LTS) is maximised. However, the experimental evidence for this prediction is weak, mainly because LTS, which indicates parasite fitness, has been difficult to measure. For castrating parasites, this simple model has been modified to take into account that parasites convert host reproductive resources into transmission stages. Parasites that kill the host too early will hardly benefit from these resources, while postponing the killing of the host results in diminished returns. As predicted from optimality models, a parasite inducing castration should therefore castrate early, but show intermediate levels of virulence, where virulence is measured as time to host killing. We studied virulence in an experimental system where a bacterial parasite castrates its host and produces spores that are not released until after host death. This permits estimating the LTS of the parasite, which can then be related to its virulence. We exposed replicate individual Daphnia magna (Crustacea) of one host clone to the same amount of bacterial spores and followed individuals until their death. We found that the parasite shows strong variation in the time to kill its host and that transmission stage production peaks at an intermediate level of virulence. A further experiment tested for the genetic basis of variation in virulence by comparing survival curves of daphniids infected with parasite spores obtained from early killing versus late killing infections. Hosts infected with early killer spores had a significantly higher death rate as compared to those infected with late killers, indicating that variation in time to death was at least in part caused by genetic differences among parasites. We speculate that the clear peak in lifetime reproductive success at intermediate killing times may be caused by the exceptionally strong physiological trade-off between host and parasite reproduction. This is the first experimental study to demonstrate that the production of propagules is highest at intermediate levels of virulence and that parasite genetic variability is available to drive the evolution of virulence in this system.     

Trade-offs in the evolution of virulence in an indirectly transmitted macroparasite

The adaptive trade-off theory for the evolution and maintenance of parasite virulence requires that virulence be genetically correlated with other fitness characteristics of the parasite. Many theoretical models rely on a positive correlation between virulence and transmissibility. They assume that high parasite replication rates are associated with a high probability of transmission (and, hence, increased parasite fitness), but also with high levels of damage to the host (high virulence). Schistosomes are macroparasites with an indirect life cycle involving a mammalian and a molluscan host. Here we demonstrate, through the development of five substrains, a genetic basis for schistosome virulence. We used these substrains further in order to investigate the presence of parasite fitness traits that were genetically correlated with virulence. High virulence in the (mouse) definitive host was, as predicted, positively correlated with parasite replication. In contrast, in the (snail) intermediate host high virulence was associated with low parasite replication rates. Variation in infectivity to and parasite replication in the definitive host was suggested as a compensating mechanism for the maintenance of virulence in the snail host. This is the first report of a trade-off in parasite reproductive success across hosts in an indirectly transmitted macroparasite.     

GENETIC RELATIONSHIPS BETWEEN PARASITE VIRULENCE AND TRANSMISSION IN THE RODENT MALARIA PLASMODIUM CHABAUDI

Many parasites evolve to become virulent rather than benign mutualists. One of the major theoretical models of parasite virulence postulates that this is because rapid within-host replication rates are necessary for successful transmission (parasite fitness) and that virulence (damage to the host) is an unavoidable consequence of this rapid replication. Two fundamental assumptions underlying this so-called evolutionary trade-off model have rarely been tested empirically: (1) that higher replication rates lead to higher levels of virulence; and (2) that higher replication rates lead to higher transmission. Both of these relationships must have a genetic basis for this evolutionary hypothesis to be relevant. These assumptions were tested in the rodent malaria parasite, Plasmodium chabaudi, by examining genetic relationships between virulence and transmission traits across a population of eight parasite clones isolated from the wild. Each clone was injected into groups of inbred mice in a controlled laboratory environment, and replication rate (measured by maximum asexual parasitemia), virulence (measured by live-weight loss and degree of anemia in the mouse), and transmission (measured by density of sexual forms, gametocytes, in the blood and proportion of mosquitoes infected after taking a blood-meal from the mouse) were assessed. It was found that clones differed widely in these traits and these clone differences were repeatable over successive blood passages. Virulence traits were strongly phenotypically and genetically (i.e., across clones) correlated to maximum parasitemia thus supporting the first assumption that rapid replication causes higher virulence. Transmission traits were also positively phenotypically and genetically correlated to parasitemia, which supports the second assumption that rapid replication leads to higher transmission. Thus, two assumptions of the parasite-centered trade-off model of the evolution of virulence were shown to be justified in malaria parasites.     

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

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

Parasite and host assemblages: embracing the reality will improve our knowledge of parasite transmission and virulence

Interactions involving several parasite species (multi-parasitized hosts) or several host species (multi-host parasites) are the rule in nature. Only a few studies have investigated these realistic, but complex, situations from an evolutionary perspective. Consequently, their impact on the evolution of parasite virulence and transmission remains poorly understood. The mechanisms by which multiple infections may influence virulence and transmission include the dynamics of intrahost competition, mediation by the host immune system and an increase in parasite genetic recombination. Theoretical investigations have yet to be conducted to determine which of these mechanisms are likely to be key factors in the evolution of virulence and transmission. In contrast, the relationship between multi-host parasites and parasite virulence and transmission has seen some theoretical investigation. The key factors in these models are the trade-off between virulence across different host species, variation in host species quality and patterns of transmission. The empirical studies on multi-host parasites suggest that interspecies transmission plays a central role in the evolution of virulence, but as yet no complete picture of the phenomena involved is available. Ultimately, determining how complex host–parasite interactions impact the evolution of host–parasite relationships will require the development of cross-disciplinary studies linking the ecology of quantitative networks with the evolution of virulence.     

Challenging the trade-off model for the evolution of virulence: is virulence management feasible?

Progress in understanding the evolution of infectious diseases has inspired proposals to manage the evolution of pathogen (including parasite) virulence. A common view is that social interventions that lower pathogen transmission will indirectly select lower virulence because of a trade-off between transmission and virulence. Here, we argue that there is little theoretical justification and no empirical evidence for this plan. Although a trade-off model might apply to some pathogens, the mechanism appears too weak for rapid selection of substantial changes in virulence. Direct selection against virulence itself might be a more rewarding approach to managing the evolution of virulence.     

Life history and virulence are linked in the ectoparasitic salmon louse Lepeophtheirus salmonis

Models of virulence evolution for horizontally transmitted parasites often assume that transmission rate (the probability that an infected host infects a susceptible host) and virulence (the increase in host mortality due to infection) are positively correlated, because higher rates of production of propagules may cause more damages to the host. However, empirical support for this assumption is scant and limited to microparasites. To fill this gap, we explored the relationships between parasite life history and virulence in the salmon louse, Lepeophtheirus salmonis, a horizontally transmitted copepod ectoparasite on Atlantic salmon Salmo salar. In the laboratory, we infected juvenile salmon hosts with equal doses of infective L. salmonis larvae and monitored parasite age at first reproduction, parasite fecundity, area of damage caused on the skin of the host, and host weight and length gain. We found that earlier onset of parasite reproduction was associated with higher parasite fecundity. Moreover, higher parasite fecundity (a proxy for transmission rate, as infection probability increases with higher numbers of parasite larvae released to the water) was associated with lower host weight gain (correlated with lower survival in juvenile salmon), supporting the presence of a virulence–transmission trade‐off. Our results are relevant in the context of increasing intensive farming, where frequent anti‐parasite drug use and increased host density may have selected for faster production of parasite transmission stages, via earlier reproduction and increased early fecundity. Our study highlights that salmon lice, therefore, are a good model for studying how human activity may affect the evolution of parasite virulence.     

Transmission-virulence trade-offs in vector-borne diseases

Though it is commonly supposed that there is a trade-off between virulence and transmission, there is little data and little insight into what it should look like. Here, we consider the specific case of vector-borne parasites (inspired by human malaria) and analyse an embedded model to understand how specific life-cycle aspects may affect this trade-off. First, we find that, for such parasites, the transmission function may have an S-shape. Second, we find that the trade-off obtained for vector-borne parasites is less sensitive to parameter variations than the trade-off obtained for directly transmitted parasites. Third, we find that other parasite traits, such as the conversion from replicative to infective stages, could have important epidemiological implications. Finally, we compare the effect of treatments targeting either the asexual or the sexual parasite life-stage.     

An empirical study of the evolution of virulence under both horizontal and vertical transmission

According to current thinking, a parasite's transmission mode will be a major determinant of virulence, defined as the harm induced by parasites to their hosts. With horizontal transmission, virulence will increase as a byproduct of a trade-off between fitness gained through increased among-host transmission (infectivity) and fitness lost through increased virulence. With vertical transmission, virulence will decrease because a parasite's reproductive potential will be maximized only by decreasing harm to the host, allowing parasite transmission to more host offspring. To test both predictions, we transmitted barley stripe mosaic virus (BSMV) horizontally and then vertically in its host, barley (Hordeum vulgare). After four generations of horizontal transmission, we observed a nearly twofold increase in horizontal infectivity and nearly tripled virulence. After three generations of subsequent vertical transmission, we observed a modest (16%) increase in vertical transmissibility and a large (40%) reduction in virulence. Increased horizontal transmission is often due to increased pathogen replication which, in turn, causes increased virulence. However, we found no correlation between within-host virus concentration and virulence, indicating that the observed changes in virulence were not due to changes in viral titer. Finally, horizontally transmitted BSMV had reduced vertical transmission and vertically transmitted BSMV had reduced horizontal infectivity. These two observations suggest that, in nature, in different host populations with varying opportunities for horizontal and vertical transmission, different viral strains may be favored.     

Virulence‐driven trade‐offs in disease transmission: A meta‐analysis*

The virulence–transmission trade‐off hypothesis proposed more than 30 years ago is the cornerstone in the study of host–parasite co‐evolution. This hypothesis rests on the premise that virulence is an unavoidable and increasing cost because the parasite uses host resources to replicate. This cost associated with replication ultimately results in a deceleration in transmission rate because increasing within‐host replication increases host mortality. Empirical tests of predictions of the hypothesis have found mixed support, which cast doubt about its overall generalizability. To quantitatively address this issue, we conducted a meta‐analysis of 29 empirical studies, after reviewing over 6000 published papers, addressing the four core relationships between (1) virulence and recovery rate, (2) within‐host replication rate and virulence, (3) within‐host replication and transmission rate, and (4) virulence and transmission rate. We found strong support for an increasing relationship between replication and virulence, and replication and transmission. Yet, it is still uncertain if these relationships generally decelerate due to high within‐study variability. There was insufficient data to quantitatively test the other two core relationships predicted by the theory. Overall, the results suggest that the current empirical evidence provides partial support for the trade‐off hypothesis, but more work remains to be done.     

The role of trade-off shapes in the evolution of parasites in spatial host populations: an approximate analytical approach

Given the substantial changes in mixing in many populations, there is considerable interest in the role that spatial structure can play in the evolution of disease. Here we examine the role of different trade-off shapes in the evolution of parasites in a spatially structured host population where infection can occur locally or globally. We develop an approximate adaptive dynamic analytical approach, to examine how the evolutionarily stable (ES) virulence depends not only on the fraction of global infection/transmission but also on the shape of the trade-off between transmission and virulence. Our analysis can successfully predict the ES virulence found previously by simulation of the full system. The analysis confirms that when there is a linear trade-off between transmission and virulence spatial structure may lead to an ES virulence that increases as the proportion of global transmission increases. However, we also show that the ESS disappears above a threshold level of global infection, leading to maximization. In addition just below this threshold, there is the possibility of evolutionary bi-stabilities. When we assume the realistic trade-off between transmission and virulence that results in an ESS in the classical mixed model, we find that spatial structure can increase or decrease the ES virulence. A relatively high proportion of local infection reduces virulence but intermediate levels can select for higher virulence. Our work not only emphasizes the importance of spatial structure to the evolution of parasites, but also makes it clear that situations between the local and the global need to be considered. We also emphasize the key role that the shape of trade-offs plays in evolutionary outcomes.     

Estimating transmission potential in gastrointestinal nematodes (order: Strongylida)

Microparasite virulence (the potential to cause harm in the host) is thought to be regulated by a direct trade-off with pathogen transmission potential, but it is unclear whether similar trade-offs occur in macroparasites (helminths). In this analysis, the transmission potentials of 5 nematode species (order Strongylida), known to differ in their virulence, were estimated using an index based on egg production and larval survivability. Virulence estimates were based on the minimum number of worms that cause host death. In nematode species where mature adults cause pathology (trichonematidic development), there is a direct relationship between virulence and transmission, suggesting that high virulence is related to parasite fitness in these worms. However, in nematodes where the juvenile stages produce pathology during migration and development (strongylidic development), virulence is not correlated with transmission. These data suggest that trade-offs between transmission and virulence in nematode parasites are not analogous for all species and may depend on the developmental strategy and mechanism of pathogenicity of the parasites.     

Virulence in malaria: an evolutionary viewpoint

Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.     

Experimental evaluation of the relationship between lethal or non-lethal virulence and transmission success in malaria parasite infections

Background  

Evolutionary theory suggests that the selection pressure on parasites to maximize their transmission determines their optimal host exploitation strategies and thus their virulence. Establishing the adaptive basis to parasite life history traits has important consequences for predicting parasite responses to public health interventions. In this study we examine the extent to which malaria parasites conform to the predicted adaptive trade-off between transmission and virulence, as defined by mortality. The majority of natural infections, however, result in sub-lethal virulent effects (e.g. anaemia) and are often composed of many strains. Both sub-lethal effects and pathogen population structure have been theoretically shown to have important consequences for virulence evolution. Thus, we additionally examine the relationship between anaemia and transmission in single and mixed clone infections.     

Transmission-recovery trade-offs to study parasite evolution

Parasite evolution is mainly studied through a trade-off involving host death (i.e., virulence) and transmission. In addition to the lack of evidence, this trade-off largely fails to understand the evolution of sublethal parasite effects. Here, I argue that considering host recovery as a main selection pressure faced by the parasite helps to address these problems and opens new perspectives for the study of parasite evolution. Using an embedded model, I show how a trade-off between transmission and recovery may emerge from within-host dynamics if immune activation is assumed to depend on the parasite's overall growth rate. I also show that the value of the parasite's optimal growth rate strongly depends on the immunological state of the host. Transmission-recovery trade-offs are of particular interest to the study of the evolution of human pathogens because of the use of antipathogen treatments, which strengthens the recovery constraint.     

Virulence not only costs but also benefits the transmission of a fungal virus

Current theory suggests that cost-benefit relationships govern the evolution of parasite virulence. The cost of virulence is expected to be high for fungal viruses, which are obligate parasites and completely dependent on their hosts. The majority of fungal viruses infect their hosts without any apparent symptoms. Cryphonectria hypovirus 1 (CHV-1), in contrast, is virulent and debilitates its host, Cryphonectria parasitica. However, the virulence of CHV-1 is associated with high costs for virus transmission, such as an attenuated fungal growth and reduced production of the fungal spores spreading the virus. In this study, we tested the hypothesis that virulence may not only have costs but also benefits for transmitting CHV-1 across vegetative incompatibility barriers between fungi. We investigated viruses with low, medium, and high virulence, and determined their transmission rate per host-to-host contact (transmissibility). The average transmission rate across all combinations tested was 53% for the most virulent virus, 37% for the virus with intermediate virulence, and 20% for the virus with lowest virulence. These results showed that increased virulence was strongly correlated with increased transmissibility, potentially counterbalancing virulence costs. This association of virulence and transmissibility may explain why CHV-1 spread widely and evolved higher virulence than most other fungal viruses.     

Temperature-dependent costs of parasitism and maintenance of polymorphism under genotype-by-environment interactions

The maintenance of genetic variation for infection-related traits is often attributed to coevolution between hosts and parasites, but it can also be maintained by environmental variation if the relative fitness of different genotypes changes with environmental variation. To gain insight into how infection-related traits are sensitive to environmental variation, we exposed a single host genotype of the freshwater crustacean Daphnia magna to four parasite isolates (which we assume to represent different genotypes) of its naturally co-occurring parasite Pasteuria ramosa at 15, 20 and 25 degrees C. We found that the cost to the host of becoming infected varied with temperature, but the magnitude of this cost did not depend on the parasite isolate. Temperature influenced parasite fitness traits; we found parasite genotype-by-environment (G x E) interactions for parasite transmission stage production, suggesting the potential for temperature variation to maintain genetic variation in this trait. Finally, we tested for temperature-dependent relationships between host and parasite fitness traits that form a key component of models of virulence evolution, and we found them to be stable across temperatures.