Abstract
Genetically controlled resistance of Anopheles gambiae mosquitoes to Plasmodium falciparum is a common trait in the natural population, and a cluster of natural resistance loci were mapped to the Plasmodium-Resistance Island (PRI) of the A. gambiae genome. The APL1 family of leucine-rich repeat (LRR) proteins was highlighted by candidate gene studies in the PRI, and is comprised of paralogs APL1A, APL1B and APL1C that share ≥50% amino acid identity. Here, we present a functional analysis of the joint response of APL1 family members during mosquito infection with human and rodent Plasmodium species. Only paralog APL1A protected A. gambiae against infection with the human malaria parasite P. falciparum from both the field population and in vitro culture. In contrast, only paralog APL1C protected against the rodent malaria parasites P. berghei and P. yoelii. We show that anti-P. falciparum protection is mediated by the Imd/Rel2 pathway, while protection against P. berghei infection was shown to require Toll/Rel1 signaling. Further, only the short Rel2-S isoform and not the long Rel2-F isoform of Rel2 confers protection against P. falciparum. Protection correlates with the transcriptional regulation of APL1A by Rel2-S but not Rel2-F, suggesting that the Rel2-S anti-parasite phenotype results at least in part from its transcriptional control over APL1A. These results indicate that distinct members of the APL1 gene family display a mutually exclusive protective effect against different classes of Plasmodium parasites. It appears that a gene-for-pathogen-class system orients the appropriate host defenses against distinct categories of similar pathogens. It is known that insect innate immune pathways can distinguish between grossly different microbes such as Gram-positive bacteria, Gram-negative bacteria, or fungi, but the function of the APL1 paralogs reveals that mosquito innate immunity possesses a more fine-grained capacity to distinguish between classes of closely related eukaryotic pathogens than has been previously recognized.
Highlights
Malaria remains a major global health problems, with more than 300 million estimated cases and more than one million deaths annually [1]
We report that of the three APL1 family members, only paralog APL1A displayed a host-protective effect against P. falciparum, which we show is mediated by a specific sub-circuit of the Rel2 signalling pathway
APL1C protects against P. berghei and P. yoelii infection We previously demonstrated that APL1 family protection against the rodent malaria parasite P. berghei was mediated only by paralog APL1C in the G3 strain of A. gambiae [9]
Summary
Malaria remains a major global health problems, with more than 300 million estimated cases and more than one million deaths annually [1]. Plasmodium falciparum is the most common human malaria parasite in Africa and is responsible for the majority of mortality due to malaria. Vector control has been one of the foundations of malaria control Recent problems such as the rapid spread of drug-resistant parasites and insecticideresistant mosquitoes have encouraged the development of a new generation of vector-based malaria control tools. Such new vectorbased strategies might be based on the introduction into the vector population of genetic information encoding novel desirable traits that reduce transmission [2], or on exploiting natural selection to promote the expansion of pre-existing desirable traits [3,4]
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