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Conceptual background of our host-parasite research

Part of the work in the Ebert group concerns the evolution and ecology of host-parasite interaction. We address this topic from a conceptual prespective and conduct empirical research on parasites of crustaceans of the genus Daphnia.

Parasites, here broadly defined as damage-producing organisms, including microbial pathogens, traditional parasites and small herbivores, are ubiquitous and influence either directly or indirectly almost every conceivable level of biological organization. The impact parasites have on the evolution and ecology of their hosts depends on their virulence, the driving force in host-parasite coevolution. Virulence, per se beneficial for neither parasite nor host, cannot be a property of a parasite alone, it is a product of the host-parasite interaction. Different host genotypes from the same population do not suffer equally when infected with the same parasite strain and different parasite strains cause variable levels of virulence in the same host genotype. Most studies on the evolution of virulence have concentrated on parasite evolution, assuming that virulence is maintained by genetic trade-offs between virulence and other fitness components of the parasite. For example, parasite-induced host mortality was shown to be negatively correlated with host recovery rate (which contributes to parasite mortality) in Australian rabbits infected with the myxoma virus and positively correlated with the multiplication rate of a microsporidian parasite in Daphnia hosts. Therefore, it has been suggested that to maximize fitness, a parasite should optimize the trade-off between virulence and other fitness components. This optimality concept for the evolution of virulence, however, largely neglects genetic variation among hosts in their interaction with parasites. Such variation results in differential reproductive success among hosts and would, in the absence of parasite evolution, select for reduced virulence. Given the high evolutionary rate of parasites, host evolution can often be ignored in a first approximation, but for a better understanding of the evolution of virulence it is essential to understand the host's evolutionary response and in particular the role of genetic recombination for host evolution.

It has been suggested that sexual reproduction of hosts is a means to overcome the disadvantage of the low evolutionary rate that an asexual host would have in comparison with its rapidly evolving parasites. Combining current theory of the advantage of genetic recombination and outbreeding with the theory on the evolution of virulence, one would predict that hosts continuously evolve to reduce virulence, while their parasites evolve to keep virulence as close as possible to an optimal level for their own life histories. In this arms-race a high evolutionary rate would benefit both opponents. Since parasites already have a very high evolutionary rate intrinsic to their short life cycle, hosts would be selected for increased evolutionary rates, even if this has costs. Sexual recombination could provide such an increase. The principle underlying assumption for this hypothesis is that within populations, genetic variation for host-parasite interaction exists and gives differential fitness to both the host and the parasites. Such genetic variation has been shown for different host-parasite systems, including variation at the major-histocompatibility complex (MHC) in relation to infectious diseases in humans (severe cerebral malaria and chronic lyme arthritis). Given continuance of such variation, genetic recombination creates novel gene combinations. In a sexual population, every host constitutes a genetically unique environment for the parasite. Therefore, parasite adaptation to one host genotype is only of temporary benefit. Thus, host diversity hinders evolution towards an optimal level of virulence and we expect a level reflecting not only the evolution of the parasite to optimize host damage, but also the evolution of the host to minimize damage.

Observing the evolution of virulence

The hypothesis that virulence in naturally coevolving populations is on average sub-optimal for the parasite allows us to make testable predictions. If host evolution is experimentally restricted by reducing host genetic variability, parasites would adapt to the predominant host genotype by shifting virulence upwards, toward their optimum. There is some empirical evidence that virulence increases during adaptation to a new host genotype. Influenza virus increases in virulence and multiplication rate when propagated experimentally within chickens with the same genetic background. Virulence of the measles virus increases when transmission occurs between siblings, as compared to non-related members of the same host population. The primate malaria agent Plasmodium knowlesi initially causes mild infections in humans. However, after 170 artificial man to man transfers, its virulence had risen sharply, indicating its adaptation to the new host environment. The well known case of initial decrease of virulence of the myxoma virus in Australian rabbits does not contradict this. The above prediction assumes that host and parasites are in a dynamic balance and it is when this holds that slower evolutionary change of the host will allow the parasite to increase virulence. The myxoma virus, however, was released to control rabbits and was therefore chosen to be as deadly as possible. Since it was in a non-natural host the optimal level of parasite virulence was far off the optimum, in this case far above the optimum. The strong decline of myxoma virus virulence over the first few years after its release indicates the strong potential of parasites to respond to changes in its genetic environment. Although ecological factors might have contributed to the described changes in virulence, adaptation to the novel host genotype appears to us to be the more likely explanation.

The adaptation of a parasite to a new host genotype not formerly common or even present, often results in the loss or a decline of virulence in relation to the host of origin. This finding was used in the development of vaccines, by employing strains in immunization programs, which became non-virulent for their normal host after being kept for some time in foreign hosts (for example against yellow fever virus and poliovirus). The loss of adaptation to different host genotypes was also shown in an originally unspecific parasitic nematode of four Drosophila species. This nematode evolved specificity only for the host species on which it was kept during the previous 50 generations, while the wild type was still able to infect all four host species. These observations emphasize the dynamic, 'Red Queen' nature of host-parasite interactions.

Local adaptation

Support for the coevolutionary hypothesis of virulence also comes from studies using the reverse of the above argument. A parasite which infects a novel host (a host of a different genotype or population than that to which the parasite is adapted) should have, on average, a lower virulence in this new host, compared to its original host. In nearly all experiments where parasites were brought experimentally into contact with novel hosts, virulence and transmissibility decreased. This has been shown for viruses, helminths, protozoans and herbivores. The reduction in virulence and transmissibility was stronger the more the novel hosts differed genetically from the host with which the parasite was associated before the experiment. Experiments which did not find significant advantages for the local parasite, showed very high levels of genetic interactions between hosts and parasites and this could contribute to the masking of local adaptation. Failure to detect local adaptation in cases where it is present can have various causes. Statistical power is weak when the within 'genetic unit' (e.g. host population, geographic area) variation is much larger than the variation explained by genetic isolation. Misjudgment of the scale of local adaptation midge also lead to problems. For example, if parasites adapt to individual hosts rather then to host populations, detection of local adaptation across host populations might be difficult. Other factors which can cause problems are acquired immunity of hosts maternal effects on resistance, asymmetric gene flow between populations (source and sink populations) and insufficient time for adaptation. To our knowledge, no evidence has been presented against local adaptation.

Attention-attracting as they may be, cases where parasites showed devastating effects after having been accidentally introduced into new host populations (e.g. rinderpest in Africa, Dutch elm disease, chestnut blight, HIV), appear to be exceptions. There are likely to have been numerous failed introductions, which have passed unnoticed. Most studies conducted under controlled conditions (see above) clearly show that parasites cause, on average, most harm in the host populations to which they are adapted to.

Testing the Red Queen hypothesis

In summary, genetic diversity of host populations appears to be crucial in hindering the parasite to evolve an optimal level of virulence. Sexual recombination benefits an outcrossing host through the production of variable offspring. Among the offspring some are better and some worse but (1) in this context novelty and rarity of genotypes have intrinsic advantages, and (2) selection leads to the propagation of what is best. Asexual offspring, in contrast, cannot escape the antagonistic advances made during the previous generations by their parent's parasites. Genetic variability among hosts forces a parasite to adapt anew whenever it encounters a new host genotype. The more different genotypes a host population consists of, the lower the frequency of each and the smaller the chance that a parasite will encounter the same genotype in successive hosts.

So far, direct evidence for the benefits of genetic diversity for host populations is weak, although numerous studies suggest such benefits. The vulnerability of mono-cultures to pathogen attack is notorious. Cereal mono cultures are shown to be more prone to attack by rapidly-evolving, clone-specific, fungal diseases than genetically mixed cultures. Also, virulence of viruses was suggested to be higher in human populations with low genetic diversity at their MHC than in MHC diverse populations. Studies in natural populations are difficult, because frequency dependence of the host-parasite arms race is time-lagged, and therefore one cannot expect a positive correlation between the parasite prevalence and frequency of host clones.

The theory that sex is advantageous in the presence of rapidly evolving parasites became known as the Red Queen hypothesis. Support for the 'sex against parasites' hypothesis has come mainly from comparative studies. Experimental studies are so far limited, with some support coming from experiments with herbivores on long-lived plants. There is a strong need for experimental studies testing predictions to clarify our understanding of arms-races and the advantage of outbreeding. We try to disect the host-parasite arms race into its components. We use a clonal host and parasite system, which allows us experimentally to freeze the evolution of one of the antagonists while allowing the other to evolve. We hope with this method to gain insight into the ever changing interactions which evolve in natural host-parasite systems.