Investment by host and parasite

It is likely that genotype-by-genotype interactions reflect the host's limitations in recognizing a parasite. Once the parasite is recognized and the host mounts an immune response in an attempt to clear it, the outcome of this immune response depends on a further interaction between the host and the parasite, for it is determined not only by the strength of the immune response but also by the ability of the parasite to avoid it. Indeed, as illustrated by the study summarized below, malaria parasites can suppress the mosquito's mela-nization response. Although this study involves a malaria/mosquito combination that does not occur in nature—the parasite Plasmodium gallinaceum in the mosquito Aedes aegypti—it is useful to indicate a potential evolutionary response.

10.3.2.1 Immunosuppression

Mosquitoes were blood-fed on an uninfected chicken or on one infected with malaria, and inoculated with a Sephadex bead 1, 2, or 4 days after blood-feeding; that is, when the ookinete is in the process of migrating through the midgut wall, when the oocyst is being established, or when the oocyst has gone through about half of its development (Figure 10.1). About 40% of the uninfected mosquitoes, but less than 25% of the infected ones, melanized the bead (Boete et al, 2002). The difference between infected and uninfected mosquitoes was most obvious 1 day after infection (at the parasite's ookinete stage), the difference diminished during the early oocyst stage (2 days after infection), and it disappeared at the later oocyst stage (4 days after infection) (Figure 10.3). It is striking that it is the early stages of the parasite that are also most sensitive to the mosquito's immunity (Collins et al, 1986; Vaughan et al, 1992; Gouagna et al, 1998), so that the selection pressure for immunosuppres-sion in these stages should be more intense than in older oocysts. These, in contrast to the ookinetes, appear to avoid recognition by the immune system by incorporating mosquito-derived proteins onto or into their surface capsule (Adini and Warburg, 1999). Such immune evasion by the oocysts would alleviate their need to actively suppress the encapsulation response.

These results suggest that the parasite can either actively suppress the mosquito's immune response or that it modifies the blood of its chicken host in a way that reduces the efficacy of the mosquito's immune system. A later experiment (Boete et al., 2004) suggests that it uses both mechanisms to suppress the mosquito's melanization response. With either mechanism, resistance against the parasite is determined by the interaction between the host's investment in its immune response and the parasite's ability to suppress immunity, so that resistance will be determined by a co-evolutionary process between mosquitoes and parasites.

10.3.2.2 Co-evolutionary model Let us therefore consider a mathematical model where resistance is determined by the interaction between the mosquitoes and malaria: the mosquitoes mount an immune response and the parasites suppress it (Koella and Boete, 2003b). Resistance R, here defined as the probability that a mosquito kills its malaria parasites, is determined by the

I I None ^ Patchy B Complete

Figure 10.3 Melanization response against inoculated beads. Each panel shows the proportion of infected mosquitoes and uninfected controls that melanize a bead to different degrees (no, patchy, and complete melanization). (a) Response against beads inoculated 24 h after infection (or blood-feeding); that is, when the parasite is in its late ookinete stage and most sensitive to the mosquito's melanization response. (b) Inoculation after 48 h, at an early oocyst stage. (c) Inoculation after 96 h, at a later oocyst stage (from Boëte et al., 2002).

I I None ^ Patchy B Complete

Figure 10.3 Melanization response against inoculated beads. Each panel shows the proportion of infected mosquitoes and uninfected controls that melanize a bead to different degrees (no, patchy, and complete melanization). (a) Response against beads inoculated 24 h after infection (or blood-feeding); that is, when the parasite is in its late ookinete stage and most sensitive to the mosquito's melanization response. (b) Inoculation after 48 h, at an early oocyst stage. (c) Inoculation after 96 h, at a later oocyst stage (from Boëte et al., 2002).

combination of the two strategies—the mosquito's investment x and the parasite's investment y—according to R = x(1-y). (Note that, even if the mosquitoes invests all of their resources to the melanization response (i.e. x = 1), strong suppression by the parasite can make the immune response ineffective.)

Details of the mathematical model (which combines evolutionary approaches with the epidemio-logical dynamics of malaria) and its analysis can be found in Koella and Boëte (2003b). The analysis involves three steps: (a) finding the host's optimal investment in resistance as a function of the parasite's strategy, (b) finding the parasite's optimal investment in immunosuppression as a function of the host's strategy, and (c) finding the co-evolutionary equilibrium of the two.

(a) Host's investment. As any other trait, the mosquito's evolutionary response to being parasitized balances costs and benefits. The benefits of an immune response are clear: they reduce the probability of being infected or increase the likelihood of clearing the parasite and thus reduce the detrimental effects of malaria infection. These can be substantial, at least in natural situations (as opposed to laboratory studies of unnatural host-parasite combinations; Ferguson and Read, 2002). Early stages of infection (oocysts) decrease fecundity, in particular if the infection is intense

(Hogg and Hurd, 1995, 1997). Late stages (sporo-zoites) increase mortality (Anderson et al., 2000), most probably because the sporozoites manipulate mosquitoes to increase the biting rate (and thus the rate of transmission) (Koella et al, 1998, 2002). As the ability to manipulate the biting rate increases with the intensity of infection (Koella, 1999), it is likely that the rate of mortality also increases with the number of sporozoites. Thus, there is considerable evolutionary pressure for the mosquito to invest in being resistant to malaria.

On the other hand, any costs of the immune response and resistance would constrain the evolution of resistance. Such costs include that adult mosquitoes in lines selected to resist malaria are smaller, take smaller bloodmeals, and lay fewer eggs than unselected mosquitoes (Yan et al., 1997), although such costs are not found in all experiments (Hurd et al., 2005). The melanization response itself is also costly in that it can reduce fecundity (Schwartz and Koella, 2004); again, this cost is not observed in all experiments (Voordouw et al., 2008b) or for all immune-stimulating antigens (Schwartz and Koella, 2004).

In our model, we assumed that the benefit of resistance is proportional to the probability that a mosquito becomes infected, which in turn is determined by the epidemiological dynamics of malaria (more specifically, the infected proportion of the human population). We assumed that the cost of resistance increases with the mosquito's investment in its immune responses. Finally, we assumed that evolution maximizes the mosquito's reproductive success.

The model's predictions for the host's investment are shown in Figure 10.4a. Consider first low potential of transmission (thin curve). (Potential of transmission is defined as the basic reproductive number of malaria that would be achieved in a population of mosquitoes with no resistance. It is essentially determined by the number of mosquitoes and their epidemiological parameters: biting rate and longevity.) At low levels of immunosup-pression, the host invests more in its immune response as immunosuppression increases. If immunosuppression passes a threshold, however, the cost of the immune response that would lead to a high level of resistance becomes prohibitive. Rather than paying the high cost of a very effective immune response, the host evolves less resistance at a lower cost, and uses the spare resources to reproduce before it is killed by the parasite. At the extreme, if immunosuppression is complete, there is of course no point in investing in immunity, as any level of immunity can only lead to complete susceptibility. As the potential of transmission increases (increasing thickness of lines), the host's optimal investment increases at low levels of immunosuppression, but decreases at high levels. At intermediate levels, the host can have two strategies that maximize its fitness (locally). Very high investment ensures that the parasite is cleared rapidly; low investment enables the host to reproduce efficiently. Therefore, if the parasite's investment is fixed, the host's evolutionary response depends on the initial conditions and can take it to either a very strong or a very weak immune response against malaria.

(b) Parasite's investment. The benefit of immuno-suppression is that the parasite is less likely to be killed by the host's immune response. Whereas there is no evidence for a cost of immunosuppression, the model assumes that it increases with investment. (Varying the shape of the cost function makes only minor differences to the outcome.) Following most models of parasite evolution, we assume that evolution maximizes the basic reproductive number of the parasite. The mathematical model predicts that immunosuppression should increase with increasing immune-efficacy (Figure 10.4b).

(c) Co-evolution. The co-evolutionary equilibrium is the intersection of these two curves. As at this point both partners are at their optimal strategies: the two strategies are co-evolutionarily stable. Figure 10.4c shows the co-evolutionary equilibria at the potentials of transmission given in Figure 10.4a. Several aspects of the pattern are noteworthy. First, the investment in immunity is only weakly related to resistance (Figure 10.4d). Although at the co-evolutionary equilibrium, increased investment in immunity generally implies increased resistance, over large ranges of investment resistance is almost independent of investment. Second, in the cases where the host has two locally optimal strategies, the co-evolutionarily stable strategy is at the host's lower investment, whereas the higher investment is never co-evolutionarily stable (Figure 10.4c). Third, the mosquito's investment in its immune responses is fairly low at any potential of transmission. Furthermore, as the potential of transmission increases, the mosquito's investment decreases. This is associated with a decrease of the parasite's ability to suppress the immune response and a decrease in overall resistance (Figure 10.4e).

10.3.2.3 Evidence

One of the most striking predictions of this co-evolutionary mathematical model is that, for a wide range of parameter values, mosquitoes should invest the least in their immune response in the areas with the most intense transmission (and therefore there is little evolutionary pressure for parasites to invest in suppressing the immune response). Although there are no data available to test this prediction, a recent study (Lambrechts et al., 2007) corroborates it. As mentioned above, malaria parasites (as ookinetes or young oocysts) can suppress the melanization response of their mosquito vector. Both of the described experiments were done with a malaria-mosquito combination that does not occur in nature: P. gallinaceum and A. aegypti. When a similar experiment—a comparison of the melanization response against Sephadex beads of malaria-infected and -uninfected mosquitoes— was done with a natural system (P. falciparum and A. gambiae) in an area with intense transmission, no

0.2 0.4 0.6 0. Investment of parasite

0.2 0.4 0.6 0. Investment of parasite

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0.2 0.4 0.6 0.8 Investment of parasite

0.4 0.6 Investment of host

Increasing intensity of transmission

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Resistance

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Parasite

25 50 75

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Figure 10.4 Evolutionary and co-evolutionary equilibria of the host's investment in its immune response and the parasite's investment in immunosuppression. (a) The host's optimal level of investment as a function of the parasite's investment, for various potentials of transmission (defined as the basic reproductive number of malaria that would be achieved in a population of mosquitoes with no resistance). It is essentially determined by the number of mosquitoes and their epidemiological parameters: biting rate and longevity. The solid lines give the optimal response and the dashed line shows the level of investment that minimizes reproductive success. The potential of transmission increases with the thickness of the lines. (b) The parasite's optimal level of investment as a function of the host's immune response. (c) The intersects of the host's and the parasite's optimal responses give the co-evolutionary equilibrium. The isoclines of the host and parasite show the levels of investment that maximize the host's success (solid lines), that minimize the host's success (dashed lines), and that maximize the parasite's success (dotted line). The co-evolutionary equilibria are given by the intersection of the isoclines. (d) Relationship between the host's investment in its immune response and resistance against the parasite. (e) Investment by the host and the parasite and level of resistance as a function of the potential of transmission (modified from Koella and Boete, 2003b).

immunosuppression was observed (Lambrechts et al., 2007). Although the difference in results may be due to many factors, one possibility is that the lack of immunosuppression in this natural system is the co-evolutionary equilibrium. Indeed, this might also help us to understand the general lack of a melanization response against malaria parasites in natural populations.

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