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 infection. These responses were analyzed by comparing mouse lines deficient for the gamma interferon (IFN-gamma) receptor (IFN-gammaR(-/-)) or deficient for inducible nitric oxide synthase (iNOS(-/-)). Both lines were highly susceptible, with similar and dramatically increased parasite burdens and severe histopathology and were incapable of surviving even very low doses, exhibiting similar mortality kinetics. This pathophysiological correlation has a common cause, since both mutant mouse strains were unable to respond to infection by producing nitric oxide (NO) with the consequence that mutant macrophages had impaired trypanocidal 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 acute infection with T. cruzi. Despite this defect, both mutant mouse strains 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-1alpha response in IFN-gammaR(-/-) mice, demonstrating that only the latter two cytokines are dependent on IFN-gamma activation. Moreover, polarization of T cells in type 1 and type 2 T-helper (Th1/Th2) and cytotoxic T (Tc1/Tc2) cells as well as T. cruzi-specific antibody responses were normal in IFN-gammaR(-/-) mice, demonstrating that IFN-gamma is not necessary for the promotion of T-cell differentiation and T. cruzi-specific antibody responses.
Hölscher
C
C
Max Planck Institute for Immunobiology, Freiburg, Germany.
Köhler
G
G
Müller
U
U
Mossmann
H
H
Schaub
G A
GA
Brombacher
F
F
D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D014355:Chagas Disease / Q000276:immunology*; D007375:Interleukin-1 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D018512:Parasitemia / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000096743:Interferon gamma Receptor
D000913:Antibodies, Protozoan; D007375:Interleukin-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C496317:Nos2 protein, mouse