The leucine-rich repeat immune protein family in malaria vector mosquitoes

Abstract

A novel mosquito-specific family of leucine-rich repeat immune proteins (LRIMs) was recently identified in Anopheles gambiae, the major vector of malaria in Africa. The founding family members, LRIM1 and APL1C, form a heterodimer circulating in the mosquito hemolymph and mediate killing of malaria parasites through their interaction with the complement C3-like effector, TEP1. This PhD thesis investigated the role of the LRIM family in mosquito immunity. Transcriptional profiling demonstrated that different LRIMs show distinct responses to malarial, fungal, bacterial and viral infections as well as to blood feeding. Certain LRIMs are broadly induced whereas others respond specifically to particular immune challenges, suggesting that there is specificity within the LRIM family towards different infections. RNA interference-mediated gene silencing identified LRIM9 as a novel antagonist of the rodent malaria parasite, Plasmodium berghei, with a putative role in parasite melanisation. Silencing LRIM9 partially inhibits the activity of phenoloxidase, a key enzyme in the melanisation pathway, but does not affect tissue melanisation. Unlike the LRIM1/APL1C heterodimer, LRIM9 circulates as a monomer in the mosquito hemolymph and is not involved in antibacterial defence. As LRIM9 does not interact with TEP1 and is not involved in TEP1 activity against Plasmodium, its precise function in the mosquito immune system remains unclear. Importantly, LRIM9 is highly upregulated in female mosquitoes after blood feeding but does not function in mosquito reproduction. The findings reported in this thesis indicate that the LRIM family has diversified to respond to infections with different microbes that mosquitoes encounter in their blood feeding lifestyle. LRIM9 is an important novel candidate for involvement in defence against malaria parasites. We hypothesise that LRIM9 is induced after blood feeding in anticipation of blood-borne infections, which is an original concept in mosquito immunity.