Cross-species TNF-α signaling in mosquitoes promotes malaria transmission

Abstract The interactions between innate immune responses in mammals and insects on vector-borne disease transmission are poorly understood. This study reveals that host-derived tumor necrosis factor α (TNF-α) binds to the mosquito receptor Wengen (Wgn), promoting the transmission of both rodent and human malaria. This TNF-α/Wgn signaling acts through mosquito TNF receptor-associated factor 3 (mTRAF3), which inhibits mosquito immune deficiency (IMD) pathway-related molecules by targeting transforming growth factor-β-activated kinase 1 (mTAK1), leading to decreased thioester-containing protein 1 (TEP1) production and increased parasite infection in mosquitoes. Additionally, neutralizing host-derived TNF-α by an anti-TNF-α antibody prevents experimental cerebral malaria (ECM) and enhances the effectiveness of an anti-Pfs25 antibody in blocking transmission. Our findings uncover a novel strategy by which host-derived TNF-α can be utilized by the parasite to facilitate its transmission, offering new avenues for preventing cerebral malaria and reducing malaria transmission.