: Inducible nitric oxide synthase (NOS II) is a vital weapon in the anti-pathogen arsenal of both mammalian and invertebrate cells. In mammals, transforming growth factor-?1 (TGF-?1) modulates the host response to pathogens such as Plasmodium, the causative agent of malaria, via a prominent role in the regulation of NOS lI. High levels of NO appear to activate latent TGF?1 by S-nitrosation and subsequent inactivation of the endogenous neutralizer of TGF-?1 (the latency-associated peptide, LAP), while free heme, a potent pro-oxidant released in certain disease states, provides an additional mechanism for activation of latent TGF-?1. Among invertebrates, Anopheles mosquitoes limit malaria parasite development with an inducible synthesis of NO that is localized principally to the midgut. Anopheles stephensi NOS (AsNOS) shows remarkable conservation with vertebrate NOS genes; however, little is known about how AsNOS is regulated. Our Preliminary Studies reveal that human TGF?1, ingested by A. stephensi and activated in the midgut, regulates AsNOS and Plasmodium development. We have also identified a mosquito TGF-? homolog, As60A, whose expression is induced in the midgut and correlated with parasite infection, indicating that like its vertebrate counterpart TGF-?1, As60A is a marker of the host response to parasite infection. The act of blood feeding by Anopheles, therefore, creates a functional interface among vertebrate and invertebrate immune factors including AsNOS, NO, TGF-?1, and As60A in the midgut environment. We hypothesize that, in the mosquito midgut, (1) mammalian TGF-?1 is activated by heme released during blood digestion and induced mosquito NO and (2) that TGF-?1 and As60A activate intersecting signaling pathways to regulate target gene expression and parasite development. At a basic level, the studies proposed herein will establish whether cytokine control is a conserved feature of immune gene regulation among organisms that are separated by more than 500 million years of evolution. At a more applied level, the proposed research will likely have implications for the control of malaria. ? ?
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