Disseminated and rapidly fatal tuberculosis in mice bearing a defective allele at IFN regulatory factor 8.
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.
Marquis
Jean-François
JF
Centre for the Study of Host Resistance, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
LaCourse
Ronald
R
Ryan
Lynn
L
North
Robert J
RJ
Gros
Philippe
P
D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001120:Arginine / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics*; D007372:Interferons / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D014774:Virulence; D000099185:Interferon Regulatory Factor-8
D001120:Arginine; D003545:Cysteine; D050835:Interferon Regulatory Factors; D007372:Interferons; D000099185:Interferon Regulatory Factor-8