Introduction

Parasites can impose strong selection on their hosts, leading to the evolution of various defence mechanisms. One of the main ones in many organisms is the immune system, which helps to protect against a wide and, to some degree, unpredictable range of parasites. Despite its obvious importance, the immune system's efficacy varies considerably within and among species. The general mechanism underlying the variation is considered to be that evolution balances the benefits and the costs of an immune response and that both vary according to the epidemiological and environmental situations (Schmid-Hempel, 2005). The benefits of the immune system are obvious (at least qualitatively): it protects against debilitating parasites. Its costs are also becoming established in many systems (Sheldon and Verhulst, 1996): mounting an immune response (in the absence of parasitic infection) can increase mortality (Moret and Schmid-Hempel, 2000), decrease fecundity (Schwartz and Koella, 2004), and lead to changes in behaviour (Mallon et al., 2003). Mechanisms leading to such evolutionary costs include the requirement by immune responses for energy and other resources (Lochmiller and Deerenberg, 2000), the risk of auto-immunity (Sadd and Siva-Jothy, 2006), or the risk that they themselves (in particular if they are over-expressed) cause the symptoms of severe disease (Margolis and Levin, 2008). Even if an immune response is not mounted in response to an infection, the immune system can be costly because of the underlying physiological machinery that must be maintained. This can lead to genetic correlations and trade-offs with important life-history parameters, such as fecundity (McKean et al., 2008) or developmental time (Koella and Boete, 2003a).

Evolutionary biologists have studied the variation of immune responses and their costs and benefits with respect to two main underlying questions. How much should an individual invest in its resistance against parasites? Does immune function indicate an individual's quality, which can, for example, help potential sexual partners to choose their mates?

In this chapter I argue that, although estimates of costs and benefits of immune responses are indispensable to understand the evolution of immune responses and thus resistance against parasitic infection, they are not enough to answer our evolutionary questions. The main point underlying my argument is that the immune system and its interaction with parasites are complex, so the relationship between immune function and resistance (and, thus, a host's quality) is not straightforward. A strong immune response need not always lead to effective resistance or a high cost. It is perhaps such complexity that leads some immune responses to be positively, others to be negatively, related to sexual attractiveness (Rantala and Kortet, 2003).

I discuss two aspects of the complexity underlying immunity and resistance. First, the immune system has many components that interact with and regulate each other to fight infection. Choosing a marker of immune function from this dynamic interplay is problematic. Markers may well be related to resistance of a given parasite, but are not used to resist other parasites (whether these are other species or other genotypes of the same species) (Adamo, 2004). Indeed, markers of immune function can be associated with increased susceptibility rather than resistance, if branches of the immune system are regulated by trade-offs. In mammals an example of such a trade-off is the reciprocal down-regulation of T-cell types Th1 and Th2 (Abbas et al., 1996). In this case, the Th2 response, say, may be associated with increased susceptibility to a parasite that is resisted via a Th2-type response. Indeed, parasites have evolved to utilize this trade-off. Leishmania major parasites, which infect macrophages and are susceptible to the Th1 response, manipulate macrophages to augment the Th2-type T-cell response (Chakkalath and Titus, 1994); they stimulate an immune response that is not only ineffective but that also suppresses the effective immune response. In invertebrates, such trade-offs are less well characterized and results are not yet conclusive. Although some components of the melanization response and an antibacterial response are negatively correlated (Cotter et al., 2004), the phenotypic outcome of the two responses—melanization of beads or clearing bacteria—are positively (genetically) correlated (Lambrechts et al., 2004). Thus, without detailed knowledge of the immune responses that help to resist a specific parasite we risk choosing markers of immune function that are, at best, evolutionar-ily irrelevant and, at worst (if they are traded off), misleading for our goal to understand resistance (Adamo, 2004; see also Chapter 11 in this volume). To make matters worse, the costs of immune function are also more complex than is generally acknowledged. In particular, they depend not only on the level of the stimulated immune response, but also on the antigen (and thus, in some cases, on the genetic variant the parasite) that stimulated it (Schwartz and Koella, 2004). Second, resistance is the outcome of the interaction between a host and a parasite; each partner can have some genetic control over the outcome and therefore the level and variation of resistance within a population is determined by a co-evolutionary process. That resistance is determined by the interaction of the two partners' genotypes means that any level of investment in immunity can lead to widely differing l evels of resistance (which depends on the parasite's traits). A perhaps more important consequence is that considering the evolution of only one of the two partners is not only insufficient to understand resistance, but may well be misleading (Restif and Koella, 2003).

Below I consider these two points with a specific example: the resistance of mosquitoes to malaria parasites. Understanding immune responses and resistance are particularly important for this system, as there is considerable interest in developing techniques to use genetically manipulated mosquitoes for the control of malaria. If mosquitoes can be transformed with genes that make them resistant and if these genes then spread through mosquito populations, it may be possible to block the parasite's transmission (Alphey et al., 2002). This goal has stimulated extensive (mostly molecular) research on the immune responses of mosquitoes (see the reviews in Dimopoulos et al., 2001; Blandin and Levashina, 2004), with the underlying assumption that effective immunity is equivalent to resistance. (Whereas some studies consider artificial peptides that are not part of the natural immune response, e.g. SM-1 (e.g. Ito et al., 2002; Moreira et al., 2004), they do not circumvent questions about their relationship with resistance, their costs, and the parasite's co-evolutionary response.) If, however, immune function is only weakly related to resistance, the approach may be problematic. Although the first problem—that it is difficult to find the immune responses that make mosquitoes resistant against a malaria parasite—may be overcome by detailed studies of immune function, the second appears more critical. If the parasite has some level of genetic control over the level of resistance achieved by a specific immune response, evolutionary pressure is likely to let it avoid any immune response that becomes dominant through the tools of genetic manipulation.

I discuss the relationship between immune function and resistance by reviewing some of the large number of studies on the interaction between malaria and mosquitoes. In particular, I discuss the relationship between effective immune responses in a laboratory setting and in natural situations, and the interaction between the mosquito's and the parasite's genotypes that determine resistance. I then discuss the importance of co-evolution in determining resistance by reviewing a theoretical model of the interaction between the mosquito and the malaria parasite. The model assumes that the parasite can counter the mosquito's allocation to immunity and that resistance results from the relative strengths of the two partners' responses.

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