The major role of the REL2/NF-κB pathway in the regulation of midgut bacterial homeostasis in the malaria vector Anopheles gambiae.

Multicellular organisms harbor diverse microbial communities that play essential roles in host physiology. While often beneficial, these interactions require tight regulation to prevent dysbiosis and disease. This study examines the tissue-specific immune responses of mosquitoes to blood feeding and Plasmodium falciparum infection in Anopheles females. We demonstrate that REL2 regulates the expression of antimicrobial peptide genes and shapes midgut bacterial composition post-blood meal. Loss of REL2 leads to midgut dysbiosis, characterized by the overgrowth of Serratia spp., and mosquito lethality after blood feeding. Interestingly, Serratia-induced dysbiosis also reduces P. falciparum prevalence in surviving mosquitoes. Our findings highlight the critical role of the immune system in maintaining midgut bacterial homeostasis and uncover complex interactions between mosquito immunity, gut microbiota, and malaria parasites.