|Pakpour, Nazzy -|
|Green, Gabriel -|
|Smithers, Hannah -|
|Cheung, Kong -|
|Riehle, Michael -|
|Luckhart, Shirley -|
Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 22, 2012
Publication Date: June 1, 2012
Citation: Pakpour, N., Corby-Harris, V.L., Green, G.P., Smithers, H.M., Cheung, K.W., Riehle, M.A., Luckhart, S. 2012. Ingested human insulin inhibits the mosquito NF-kB-dependent immune response to Plasmodium falciparum. Infection and Immunity. 80(6):p. 2141-2149. DOI:10.1128/IAI.00024-12 Interpretive Summary: In previous work, we showed that insulin signaling pathways are induced in Anopheles stephensi mosquitoes fed human insulin, a component of vertebrate blood. Induction of this pathway causes increased susceptiblity to malaria (Plasmodium falciparum) infection, but the mechanisms underlying this pattern have not been demonstrated. Here, we show that insulin signaling in mosquitoes reduced immune signaling, causing the malaria parasite to grow and develop better in the host. Our data suggest that by feeding on vertebrate blood, insulin signaling is up-regulated in A. stephensi mosquitoes, causing increased susceptibility to malaria infection. Our data have clear implications for malaria control and for understanding how insulin signaling and immunity interact.
Technical Abstract: We showed previously that ingested human insulin activates the insulin/IGF-1 signaling pathway in Anopheles stephensi and increases the susceptibility of these mosquitoes to Plasmodium falciparum. In other organisms insulin can alter immune responsiveness through regulation of NF-kB transcription factors, critical elements for innate immunity that are also central to mosquito immunity. We show here that insulin signaling decreased expression of NF-kB-regulated immune genes in mosquito cells stimulated with either bacterial or malarial products. Further, human insulin suppressed mosquito immunity through sustained PI3K activation, as inhibition of this pathway led to decreased parasite development in the mosquito. Together, these data demonstrate that activation of the insulin/IGF-1 signaling pathway by ingested human insulin can alter NF-kB-dependent immunity, and ultimately the susceptibility, of mosquitoes to P. falciparum.