Abstract
The complement C3-like protein TEP1 of the mosquito Anopheles gambiae is required for defense against malaria parasites and bacteria. Two forms of TEP1 are present in the mosquito hemolymph, the full-length TEP1-F and the proteolytically processed TEP1cut that is part of a complex including the leucine-rich repeat proteins LRIM1 and APL1C. Here we show that the non-catalytic serine protease SPCLIP1 is a key regulator of the complement-like pathway. SPCLIP1 is required for accumulation of TEP1 on microbial surfaces, a reaction that leads to lysis of malaria parasites or triggers activation of a cascade culminating with melanization of malaria parasites and bacteria. We also demonstrate that the two forms of TEP1 have distinct roles in the complement-like pathway and provide the first evidence for a complement convertase-like cascade in insects analogous to that in vertebrates. Our findings establish that core principles of complement activation are conserved throughout the evolution of animals.
Highlights
The mosquito Anopheles gambiae is the main vector of Plasmodium falciparum malaria in sub-Saharan Africa and directly responsible for the death of hundreds of thousands of people every year and for a devastating socioeconomic burden especially in endemic countries
SPCLIP1 is a component of the complement-like pathway To identify novel components of the mosquito complement pathway, we searched for genes that exhibited significant coregulation with LRIM1 in a developmental transcriptome dataset of Expressed Sequence Tags (ESTs; [19])
We characterize SPCLIP1, a non-catalytic CLIP-domain serine protease of the malaria vector mosquito A. gambiae, which localizes to the surface of P. berghei ookinetes and E. coli promoting rapid accumulation of the complement C3-like protein TEP1
Summary
The mosquito Anopheles gambiae is the main vector of Plasmodium falciparum malaria in sub-Saharan Africa and directly responsible for the death of hundreds of thousands of people every year and for a devastating socioeconomic burden especially in endemic countries. Despite the fact that distinct TEP1 alleles have been associated with resistance to Plasmodium parasites [2,8,11,12,13], the selective pressure on TEP1 is hypothesized to be driven by pathogens in larval habitats rather than those encountered by adults. This is further supported by the rather generic immune specificity of TEP1 that functions in anti-bacterial [3,14] and anti-fungal defense [15]. A better understanding of the mechanisms regulating complement activation and identification of the proteins involved will permit deciphering the functional relevance to Plasmodium of allelic interactions within this immune module on resistance
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