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

The effects of the interactions of innate immune responses between mammals and insects on the transmission dynamics of vector-borne diseases remain poorly understood. In this study, we report that host-derived TNF-alpha selectively binds to a specific mosquito TNF-alpha receptor known as Wengen, facilitating the transmission of both rodent and human malaria. Mechanistically, the binding of host-derived TNF-alpha to Wengen activates the downstream intracellular adaptor molecule dTRAF3, which inhibits the mosquito immune deficiency (IMD)/Relish pathway by acting on dTAK1. This inhibition of the IMD pathway significantly reduces the production of TEP1, a critical effector in the mosquito immune response that targets malaria parasites. Furthermore, the neutralization of host-derived TNF-alpha could not only prevent the development of experimental cerebral malaria, but also enhance the transmission blocking efficacy of anti-pfs25. Thus, we reveal a novel strategy employed by malaria parasites to enhance their transmission by exploiting the cross-species effects of host TNF-alpha signaling in mosquitoes, and provide a novel strategy to prevent cerebral malaria and reduce malaria transmission by targeting TNF-alpha