Abstract
Anopheles gambiae melanization-based refractoriness to the human malaria parasite Plasmodium falciparum has rarely been observed in either laboratory or natural conditions, in contrast to the rodent model malaria parasite Plasmodium berghei that can become completely melanized by a TEP1 complement-like system-dependent mechanism. Multiple studies have shown that the rodent parasite evades this defense by recruiting the C-type lectins CTL4 and CTLMA2, while permissiveness to the human malaria parasite was not affected by partial depletion of these factors by RNAi silencing. Using CRISPR/Cas9-based CTL4 knockout, we show that A. gambiae can mount melanization-based refractoriness to the human malaria parasite, which is independent of the TEP1 complement-like system and the major anti-Plasmodium immune pathway Imd. Our study indicates a hierarchical specificity in the control of Plasmodium melanization and proves CTL4 as an essential host factor for P. falciparum transmission and one of the most potent mosquito-encoded malaria transmission-blocking targets.
Highlights
Plasmodium falciparum is the most prevalent malaria parasite in Africa, accounting for 99.7% of the 213 million malaria cases on that continent in 2018 [1]
Using CRISPR/Cas9 green fluorescent marker only (Cas9)-based CTL4 knockout, we show that A. gambiae can mount melanization-based refractoriness to the human malaria parasite, which is independent of the TEP1 complement-like system and the major anti-Plasmodium immune pathway immune deficiency (Imd)
These data show that CRISPR/Cas9-mediated disruption of CTL4 is complete in the guide RNAs (gRNAs)/Cas9 transheterozygotes; the F0 somatic CTL4 knockout mutants were used as a model for further studies
Summary
Plasmodium falciparum is the most prevalent malaria parasite in Africa, accounting for 99.7% of the 213 million malaria cases on that continent in 2018 [1]. A comprehensive understanding of the biology and transmission of this human-pathogenic parasite through its main mosquito vector, Anopheles gambiae, is paramount for developing new tools to control malaria. Anophelines are not passive vectors: They possess an effective innate immune system that controls infections with diverse microbes, including Plasmodium parasites, bacteria, and fungi, with some degree of specificity. The susceptibility of mosquitoes to Plasmodium and other pathogens, and, vector competence, is an intricate process determined by a fine balance between antagonistic and agonistic immune mechanisms and factors [2]. Melanization, typically the deposit of a melanin layer on the pathogen surface that results in its encapsulation, is one of the most effective insect defense mechanisms, and extensive studies have shown that A.
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