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J. Exp. Med., Volume 188, Number 8, October 19, 1998 1541-1546

Rapid Interferon gamma -dependent Clearance of Influenza A Virus and Protection from Consolidating Pneumonitis in Nitric Oxide Synthase 2-deficient Mice

By Gunasegaran Karupiah,* Jian-He Chen,* Surendran Mahalingam,* Carl F. Nathan,Dagger and John D. MacMickingDagger

From the * Host Defense Laboratory, Viral Engineering and Cytokines Group, Division of Immunology and Cell Biology, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia; and the Dagger  Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York 10021

Viral infection often activates the interferon (IFN)-gamma -inducible gene, nitric oxide synthase 2 (NOS2). Expression of NOS2 can limit viral growth but may also suppress the immune system and damage tissue. This study assessed each of these effects in genetically deficient NOS2-/- mice after infection with influenza A, a virus against which IFN-gamma has no known activity. At inocula sufficient to cause consolidating pneumonitis and death in wild-type control mice, NOS2-/- hosts survived with little histopathologic evidence of pneumonitis. Moreover, they cleared influenza A virus from their lungs by an IFN-gamma -dependent mechanism that was not evident in wild-type mice. Even when the IFN-gamma -mediated antiviral activity was blocked in NOS2-/- mice with anti-IFN-gamma mAb, such mice failed to succumb to disease. Further evidence that this protection was independent of viral load was provided by treating NOS2+/+ mice with the NOS inhibitor, Nomega -methyl-L-arginine (L-NMA). L-NMA prevented mortality without affecting viral growth. Thus, host NOS2 seems to contribute more significantly to the development of influenza pneumonitis in mice than the cytopathic effects of viral replication. Although NOS2 mediates some antiviral effects of IFN-gamma , during influenza infection it can suppress another IFN-gamma -dependent antiviral mechanism. This mechanism was observed only in the complete absence of NOS2 activity and appeared sufficient to control influenza A virus growth in the absence of changes in cytotoxic T lymphocyte activity.

Key words: nitric oxide synthase;  interferon gamma ;  virus infection;  influenza A;  cytotoxic T lymphocyte


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