Our discussion here is focused on the general features of the PRR repertoire in the mosquito A, gambiae, as representative of an insect that is exposed to a particularly broad range of microbes. The genome of the A, gambiae mosquito harbours approximately 150 germ-line-encoded PRR genes. The majority of these genes encode secreted proteins with adhesive domains that can interact with PAMPs, which are commonly lipopolysaccharides or peptidoglycans. Most mosquito PRRs have a single pattern-recognition domain, but some of them have a more complex pattern of gene organization that includes multiple domains with other functional roles, such as catalysis or signal trans-duction. All known mosquito PRRs belong to larger gene families, most of which have expanded significantly when compared to their homologues in the fruit fly Drosophila melanogaster. Quite a few A, gambiae PRRs have been functionally implicated in the mosquito's anti-Plasmodium defence and presumably participate in recognition of the parasite.
One of the most well-characterized PRRs is the thioester-containing protein 1 (TEP1), a complement-like phagocytic factor that also recognizes and associates with the malaria parasite (Levashina et al., 2001). TEP1 is produced by haemocytes and is found to colocalize with the surface of Plasmodium ookinetes in the midgut epithelium. The ligand of TEP1 appears to be ookinete-specific, since the later oocyst stages are only weakly recognized, and no association with the late sporozoite stage has been documented. Once it has interacted with the parasite, TEP1 appears to activate a powerful killing mechanism that eliminates the parasite (Blandin et al., 2004).
Another anti-Plasmodium PRR is the leucine-rich-repeat-containing protein LRIM1, which is specifically involved in killing the rodent Plasmodium berghei parasite but has no apparent effect on the human parasite, Plasmodium falcip-arum (Osta et al., 2004). The mechanism of action of LRIM1 is unknown, and its association with the parasite has yet to be demonstrated. The differential effect of this protein on the two parasite species is likely to reflect a high degree of pattern-recognition specificity.
Interestingly, not all PRRs are negative effectors with regard to pathogen development. For example, some PRRs have been shown to act as agonists with regard to infection by the rodent Plasmodium parasite. The infection-inducible C-type lectins, CTL4 and CTLMA2, have a protective effect on the parasite and prevent its melanization (Osta et al., 2004). It is likely that the P. berghei parasite associates with these lectins and uses them to camouflage itself from the mosquito's defence system. Interestingly, the protective capacity of these C-type lectins is specific for P. berghei and is not seen in the case of infection with the human pathogen, P. falciparum (Cohuet et al., 2006).
A plethora of other PRRs have also been shown to modulate Plasmodium infection in the mosquito, but their specificities and mechanisms of action are still under investigation. For instance, AgMDL1 is an A. gambiae PRR that is specific for immune defence against the human pathogen P. falciparum (Dong et al., 2006a). The mammalian homologue of AgMDL1, MD-2, recognizes lipopolysacchar-ide (LPS), and then acts as an adaptor protein that activates the Toll-like receptor 4 to initiate immune response activation. The role of AgMDL1 in either recognizing and/or defending against Plasmodium is not yet clear. Other key players in the anti-Plasmodium defence are two leucine-rich-repeat-domain-containing PRRs, APL1/LRRD19 and APL2/LRRD7, which have been shown by gene expression analysis and quantitative trait locus linkage mapping to be induced upon Plasmodium infection. These genes map to a chromosomal region that has been shown to contribute to P. fal-ciparum resistance in certain natural mosquito populations (Dong et al, 2006a; Riehle et al, 2006).
Numerous other PRRs have been linked to the anti-Plasmodium and antimicrobial defence in the mosquito, and we will more specifically focus on some of the better-studied and potentially more interesting mosquito PRR gene families. The Gram-negative-bacteria-binding protein (GNBP) gene family was one of the first mosquito PRRs to be studied, together with the peptidoglycan-recognition protein (PGRP) gene family. Members of these two PRR gene families have been implicated in immune-signalling pathway activation and will be discussed in this review in greater detail. We will also address a very large receptor gene family that includes many members with PRR function, the immunoglobulin gene superfamily (IgSF). We will finally look at two PRRs that significantly contribute to the expansion of the mosquito PRR repertoire: the Down syndrome cell-adhesion molecule (Dscam) and the members of the fibrino-gen domain immunolectin (FBN) gene family.
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