Distinct roles of the Anopheles gambiae Imd/Rel2 and Toll/Rel1 pathways in resistance to systemic bacterial and fungal infections.

In the malaria vector Anopheles gambiae s.l. Toll and Imd immune pathways signal through Re1l and Rel2 NF-κB transcription factors, respectively. Toll/Rel1 and Imd/Rel2 have been characterized mostly in the context of defense against malaria parasites, exhibiting Plasmodium species-specific roles. There is also evidence associating Rel2 with mosquito resistance to bacterial infections, however, the role of Rel1 in this context remains questionable, especially that there have been no rigorous functional genetic studies assessing Rel1 and Rel2 contributions side-by-side to mosquito defense during systemic microbial infections. Here, we conducted this analysis in An. gambiae using systemic infections with five bacterial species and the fungus Beauveria bassiana. We show that Rel2 is largely responsible for controlling the bacterial burden and for mediating mosquito tolerance to bacterial infections, whereas Rel1 contributes mainly to tolerating infections with certain bacteria, specifically those exhibiting high virulence. Rel2 is also largely responsible for regulating the expression of Cecropin 1 and Defensin 1 antimicrobial peptide genes in the fat body after bacterial systemic infections, yet in certain infections a synergistic role for Rel1 and Rel2 was also evident. In the context of fungal infections, Re1l but not Rel2 controlled the fungal burden in mosquitoes, yet resistance and tolerance to fungal infections were largely attributed to TEP1. In sum, these results advance our understanding of Imd/Rel2 and Toll/Rel1 contributions to mosquito systemic immunity and suggest that they most likely control distinct transcriptional programs in the fat body that differentially impact mosquito resistance and tolerance to systemic microbial infections.