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J Immunol. 2009 Mar 1;182(5):3008-15. doi: 10.4049/jimmunol.0800680.

Disseminated and rapidly fatal tuberculosis in mice bearing a defective allele at IFN regulatory factor 8.

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1
Centre for the Study of Host Resistance, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.

Abstract

The interferon regulatory factor (IRF) family member IRF-8 participates in IFN-gamma-dependent transcriptional activation of genes containing in their promoter regions IFN-stimulated response element or IFN-gamma 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-gamma 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.

PMID:
19234196
PMCID:
PMC4307599
DOI:
10.4049/jimmunol.0800680
[Indexed for MEDLINE]
Free PMC Article
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