TYPE-1 INTERFERON (IFN-ALPHA BETA) AND TYPE-2 NITRIC-OXIDE SYNTHASE REGULATE THE INNATE IMMUNE-RESPONSE TO A PROTOZOAN PARASITE/

Type 2 nitric oxide synthase (NOS2) is required for the Th1-dependent healing of infections with intracellular microbes, including Leishmani a major. Here, we demonstrate the expression and define the function o f NOS2 during the innate response to L. major. At day 1 of infection, genetic deletion or functional inactivation of NOS2 abolished the IFN gamma and natural killer cell response, increased the expression of TG F beta, and caused parasite spreading from the skin and lymph node to the spleen, liver, bone marrow, and lung. Induction of NOS2 was depend ent on IFN alpha/beta. Neutralization of IFN alpha/beta mimicked the p henotype of NOS2(-/-) mice. Thus, IFN alpha/beta and NOS2 are critical regulators of the innate response to L. major.