Type 1 interferon (IFNα/β) 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 Leishmania major. Here, we demonstrate the expression and define the function of 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 TGF beta, and caused parasite spreading from the skin and lymph node to the spleen, liver, bone marrow, and lung. Induction of NOS2 was dependent on IFN alpha/beta. Neutralization of IFN alpha/beta mimicked the phenotype of NOS2(-/-) mice. Thus, IFN alpha/beta and NOS2 are critical regulators of the innate response to L. major.