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Disseminated and Rapidly Fatal Tuberculosis in Mice Bearing a Defective Allele at IFN Regulatory Factor 8¹

Jean-François Marquis^*, Ronald LaCourse, Lynn Ryan, Robert J. North and Philippe Gros^2,*

^* Centre for the Study of Host Resistance, Department of Biochemistry, McGill University, Montreal, Quebec, Canada; and Trudeau Institute, Saranac Lake, NY 12983

The interferon regulatory factor (IRF) family member IRF-8 participates in IFN--dependent transcriptional activation of genes containing in their promoter regions IFN-stimulated response element or IFN- activation site elements. To test the role of IRF-8 in host defenses against tuberculosis, BXH-2 mice, which bear a defective IRF-8^R294C allele, were challenged with low doses of virulent Mycobacterium tuberculosis via the i.v. and aerosol routes. BXH-2 mice were found to be extremely susceptible to M. tuberculosis, as demonstrated by rapid and uncontrolled microbial replication in spleen, liver, and lungs leading to very early death. The BXH-2 defect was expressed very early (10 days postinfection) as uncontrolled intracellular pathogen replication in NOS2-expressing lung macrophages, impaired granuloma formation, rapid dissemination of the infection to distant sites, and rapid necrosis of infected tissues. There was complete absence of IL-12p40 induction, severely reduced IFN- production, and impaired T cell priming in the lungs of infected BXH-2, highlighting the critical role of IRF-8 in this process. Collectively, these results identify IRF-8 as a critical regulator of host defenses against tuberculosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant AI035237 (to P.G.) from the National Institutes of Health and Grant AI069161 (to R.J.N.) from the National Institute of Allergy and Infectious Diseases. P.G. is a James McGill Professor of Biochemistry and a Distinguished Scientist of the Canadian Institutes of Health Research. J.-F.M. is supported by a fellowship from the Fonds de Recherche en Santé du Québec.

² Address correspondence and reprint requests to Dr. Philippe Gros, Department of Biochemistry, McGill University, Bellini Building, 3649 Promenade Sir William Osler, Room 370, Montreal, Quebec, Canada H3G 0B1. E-mail address: philippe.gros{at}mcgill.ca

³ Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guérin; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; NOS2, nitric oxide synthase 2; MST, mean survival time; DC, dendritic cell.