Immunity and resistance

To begin, I briefly describe the development of malaria parasites in the mosquito (Figure 10.1) and consider possible mechanisms of resistance. Mosquitoes take up infectious gametocytes when they feed on a gametocyte carrier. These exflagel-late to produce male and female gametes, which mate to produce a zygote. The zygote transforms to an ookinete, which migrates through the midgut wall and implants as an oocyst. Within the oocyst, rapid replication produces sporozoite precursors. Upon completion of this developmental process, the oocyst bursts to release the sporozoites, which migrate to the mosquito's salivary glands from where they can infect the next victims of the mosquito's bites.

Mosquitoes can block this development with a variety of immune responses: by lysing the ooki-netes as they are migrating through the midgut wall (Vernick et al., 1995), by producing nitric oxide (Luckhart et al., 1998) (which impedes the development of the parasite), by melanizing ookinetes and early oocysts (Collins et al., 1986), and by killing parasites with antimicrobial peptides (Dong et al., 2006). Extensive studies in molecular biology have given us an impressive description of the genetic and molecular interactions underlying these processes (reviewed in Dimopoulos et al, 2001; Blandin and Levashina, 2004).

In the context of this chapter, there are two striking features of these molecular studies. First, functional immunity depends on a large number of genes and, in particular, on the interaction between genes. For example, knocking out either one of two receptor genes (CLIP A2 or CLIP A5) roughly halves the number of oocysts in a midgut, knocking out both decreases the number by a factor of close to 10, and knocking out an additional one (CLIP A8) brings the number back up to about a third of the unmanipulated controls (Volz et al., 2006). Second, the efficacy and the function of an immune response associated with several genes differ among mosquito species (Abraham et al., 2005; Dong et al., 2006) and depend on the genetic background of a given mosquito species. For example, Volz et al. (2006) studied several genes associated with the melanization of ookinetes. In a malaria-resistant strain of mosquitoes, these genes are responsible for the melanization and disposition of dead ookinetes, but in a malaria-susceptible strain the same genes induce a melanization response that kills the ookinetes directly.

The melanization response is an illustrative example of several important points. The first selection experiment leading to malaria-resistant mosquitoes found that resistant mosquitoes mela-nize their oocysts (Collins et al, 1986). Mosquitoes

Figure 10.1 The life cycle of malaria parasites in the mosquito.

selected for resistance have a more effective mela-nization response (estimated by the ability to mel-anize a Sephadex bead injected into the thorax, a standard and convenient method of assaying this response in mosquitoes; Paskewitz and Riehle, 1994; Chun et al, 1995; Suwanchaichinda and Paskewitz, 1998) than susceptible mosquitoes (Voordouw et al., 2008a) and the mechanisms underlying malaria resistance and melanization of Sephadex beads share at least part of their genetic determination (Gorman et al., 1996; Gorman and Paskewitz, 1997). However, despite the association between resistance and the melanization response, it is unlikely that melanization helps to resist infection in natural populations. Although mosquitoes generally show some resistance to infection (e.g. in a highly endemic region of Kenya, about 70% of mosquitoes that had fed on blood containing the gametocytes of various isolates of the parasite were not infected; Lambrechts et al., 2005), malaria parasites are almost never melanized (e.g. one in 200 infected mosquitoes in a Tanzanian study; Schwartz and Koella, 2002). Despite the ineffective melanization of malaria parasites, most mosquitoes can melanize Sephadex beads effectively (85% in the Tanzanian study; Schwartz and Koella, 2002). It is also noteworthy that non-vector species of mosquito use the melanization response to kill malaria ookinetes (Habtewold et al, 2008). Thus, mosquitoes have a functional, effective melanization response, but in vector species it cannot be used against malaria parasites. This suggests that the malaria parasite has evolved ways to either avoid being detected by the immune receptors of its vector species or to suppress its melanization response. In either case, it seems clear that at least one of the main branches of the insect immune system—the melanization response—is a bad marker of resistance to malaria. It also begs interesting evolutionary and immuno-logical questions: how and why does the malaria parasite avoid the melanization response? I discuss aspects of these questions below.

To date, despite detailed knowledge about many aspects of the mosquito's immune system, we do not know how mosquitoes resist malaria, in particular in natural populations of malaria vectors. It is likely that nitric oxide and antimicrobial peptides contribute to resistance, as in some populations the allelic variation of the genes underlying the production of nitric oxide synthase and cecropins (an antimicrobial peptide) is associated with the likelihood of infection by malaria in field-caught mosquitoes (Luckhart et al, 2003). However, in other studies on the genetic variation of resistance of African mosquitoes, none of the described quantitative trait loci associated with resistance co-localized with the genes that are known to be involved in the immunological processes described above, but suggest a role for a leucine-rich repeat protein that is similar to molecules involved in natural pathogen-resistance mechanisms in plants and mammals. Another recent study describes non-classical immune responses (activation of actin cytoskeleton dynamics and a haemolymph lipid transporter) in the resistance of mosquitoes to field isolates of malaria parasites (Mendes et al., 2008).

Overall, resistance of mosquitoes to malaria parasites appears to be the result of complex interactions among several immune processes that may be positively correlated (Lambrechts et al, 2004) or traded off (Cotter et al., 2004). Dealing with this complexity makes it difficult to reach conclusions about the evolution of the efficacy of individual immune responses. Indeed, it suggests that any immuno-logical marker would be at most a weak marker of resistance and, thus, of the mosquito's evolutionary quality. The best (and only) marker of immune function (as a response to malaria infection) may well be the mosquito's resistance to malaria parasites.

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