DEFECTIVE NITRIC-OXIDE EFFECTOR FUNCTIONS LEAD TO EXTREME SUSCEPTIBILITY OF TRYPANOSOMA CRUZI-INFECTED MICE DEFICIENT IN GAMMA-INTERFERON RECEPTOR OR INDUCIBLE NITRIC-OXIDE SYNTHASE

Trypanosoma cruzi, the causative agent of Chagas' disease, induces an innate and adaptive host immune response during the acute phase of inf ection, These responses were analyzed by comparing mouse lines deficie nt for the gamma interferon (IFN-gamma) receptor (IFN-gamma R-/-) or d eficient for inducible nitric oxide synthase (iNOS(-/-)). Both lines w ere highly susceptible, with similar and dramatically increased parasi te burdens and severe histopathology and were incapable of surviving e ven very low doses, exhibiting similar mortality kinetics. This pathop hysiological correlation has a common cause, since both mutant moose s trains were unable to respond to infection by producing nitric oxide ( NO) with the consequence that mutant macrophages had impaired trypanoc idal activities, These in vivo and subsequent in vitro studies further demonstrated that an IFN-gamma dependent pathway of iNOS induction is crucial for efficient. NO production and mandatory for resisting acut e infection with T. cruzi. Despite this defect, both mutant mouse stra ins had a rather normal proinflammatory cytokine response (interleukin -12 [IL-12], IFN-gamma, IL-6), with the exception of an impaired tumor necrosis factor alpha and IL-1 alpha response in IFN-gamma R-/- mice, demonstrating that only the latter two cytokines are dependent on IFN -gamma activation. Moreover, polarization of T cells in type 1 and typ e 2 T-helper (Th1/Th2) and cytotoxic T (Tc1/Tc2) cells as well as T. c ruzi-specific antibody responses were normal in IFN-gamma R-/- mice, d emonstrating that IFN-gamma is mot necessary for the promotion of T-ce ll differentiation and T. cruzi-specific antibody responses.