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Journal of Virology, November 1998, p. 8550-8558, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Role of Interferon in Influenza Virus Tissue Tropism

Adolfo García-Sastre,1 Russell K. Durbin,2 Hongyong Zheng,1 Peter Palese,1 Rachel Gertner,3 David E. Levy,3 and Joan E. Durbin2,*

Department of Microbiology, Mount Sinai School of Medicine, New York, New York 100291; Children's Hospital Research Foundation and Department of Pediatrics, Ohio State University, Columbus, Ohio 432052; and Department of Pathology, New York University Medical Center, New York, New York 100163

Received 9 April 1998/Accepted 14 July 1998

We have studied the pathogenesis of influenza virus infection in mice that are unable to respond to type I or II interferons due to a targeted disruption of the STAT1 gene. STAT1-/- animals are 100-fold more sensitive to lethal infection with influenza A/WSN/33 virus than are their wild-type (WT) counterparts. Virus replicated only in the lungs of WT animals following intranasal (i.n.) virus inoculation, while STAT1-/- mice developed a fulminant systemic influenza virus infection following either i.n. or intraperitoneal inoculation. We investigated the mechanism underlying this altered virus tropism by comparing levels of virus replication in fibroblast cell lines and murine embryonic fibroblasts derived from WT mice, STAT-/- mice, and mice lacking gamma interferon (IFNgamma -/- mice) or the IFN-alpha receptor (IFNalpha R-/- mice). Influenza A/WSN/33 virus replicates to high titers in STAT1-/- or IFNalpha R-/- fibroblasts, while cells derived from WT or IFNgamma -/- animals are resistant to influenza virus infection. Immunofluorescence studies using WT fibroblast cell lines demonstrated that only a small subpopulation of WT cells can be infected and that in the few infected WT cells, virus replication is aborted at an early, nuclear phase. In all organs examined except the lung, influenza A WSN/33 virus infection is apparently prevented by an intact type I interferon response. Our results demonstrate that type I interferon plays an important role in determining the pathogenicity and tissue restriction of influenza A/WSN/33 virus in vivo and in vitro.

* Corresponding author. Mailing address: Children's Hospital Research Foundation, 650 Children's Dr., Columbus, OH 43205. Phone: (614) 722-2798. Fax: (614) 722-2817. E-mail: DurbinJ{at}pediatrics.ohio-state.edu.

Journal of Virology, November 1998, p. 8550-8558, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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