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Journal of Virology, May 2002, p. 4520-4525, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4520-4525.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Promotion of Alpha/Beta Interferon Induction during In Vivo Viral Infection through Alpha/Beta Interferon Receptor/STAT1 System-Dependent and -Independent Pathways

Lene Malmgaard, Thais P. Salazar-Mather, Casey A. Lewis, and Christine A. Biron*

Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912

Received 5 October 2001/ Accepted 25 January 2002

Viruses and viral components can be potent inducers of alpha/beta interferons (IFN-{alpha}/ß). In culture, IFN-{alpha}/ß prime for their own expression, in response to viruses, through interferon regulatory factor 7 (IRF-7) induction. The studies presented here evaluated the requirements for functional IFN receptors and the IFN signaling molecule STAT1 in IFN-{alpha}/ß induction during infections of mice with lymphocytic choriomeningitis virus (LCMV). At 24 h after infection, levels of induced IFN-{alpha}/ß in serum were reduced 90 to 95% in IFN-{alpha}/ß receptor-deficient (IFN-{alpha}/ßR-/-) and STAT1-/- mice compared to those in wild-type mice. However, at 48 h, these mice showed elevated expression in the serum whereas IFN-{alpha}/ß levels were still reduced >75% in IFN-{alpha}/ß{gamma}R-/- mice even though the viral burden was heavy. Levels of IFN-ß, IFN-{alpha}4, and non-IFN-{alpha}4 subtype mRNA expression correlated with IFN-{alpha}/ß bioactivity, and all IFN-{alpha}/ß subtypes were coincidentally detectable. IRF-7 mRNA was induced under conditions of IFN-{alpha}/ß production, including late production in IFN-{alpha}/ßR-/- mice. These data demonstrate that the presence of the virus alone is not sufficient to induce IFN-{alpha}/ß during LCMV infection in vivo. Instead, autocrine amplification through the IFN-{alpha}/ßR is necessary for optimal induction. In the absence of a functional IFN-{alpha}/ßR, however, alternative mechanisms, independent of STAT1 but requiring a functional IFN-{gamma}R, take over.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Box G-B629, Brown University, Providence, RI 02912. Phone: (401) 863-2921. Fax: (401) 863-1971. E-mail: Christine_Biron{at}brown.edu.

Journal of Virology, May 2002, p. 4520-4525, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4520-4525.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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