Mosquito immune defenses against Plasmodium infection

Abstract

The causative agent of malaria, Plasmodium, has to undergo complex developmental transitions and survive attacks from the mosquito's innate immune system to achieve transmission from one host to another through the vector. Here we discuss recent findings on the role of the mosquito's innate immune signaling pathways in preventing infection by the Plasmodium parasite, the identification and mechanistic description of novel anti-parasite molecules, the role that natural bacteria harbored in the mosquito midgut might play in this immune defense and the crucial parasite and vector molecules that mediate midgut infection.

Figure 1. Toll and IMD immune signaling pathways involved in anti-Plasmodium defense

Following recognition of a microbe, or unknown Plasmodium ligand, by soluble PGRP molecules, the Toll pathway is stimulated by binding of the ligand Spätzle with the Toll transmembrane receptor. This triggers a series of molecular events that culminate in the activation (*) and translocation of Rel1 into the nucleus, up-regulating transcription of immune genes that are responsible for microbial killing. The IMD pathway is stimulated when the transmembrane PGRPLC receptor binds peptidoglycan or an unknown Plasmodium ligand that leads to the cleavage of Rel2-F and translocation of active Rel2-S (*) into the nucleus. A different set of anti-Plasmodium genes are up-regulated when the IMD pathway is stimulated. Branching of the IMD pathway is indicated, but the JNK pathway has not been extensively characterized in Anopheles mosquitoes.

Figure 2. Parasite development and anti-Plasmodium effectors in the mosquito

The Plasmodium parasite develops into the motile ookinete stage and will invade the midgut epithelium at approximately 18 hours after ingestion of an infected blood meal. At this stage, a number of effector molecules target the parasite for destruction (inset). NOS targets the parasite at a later developmental stage- the early/late oocyst transition. Effector molecules in underlined bold are involved in killing human and rodent Plasmodium species, those in bold italics have been shown to be effective against P. berghei only, and those in bold target P. falciparum.