Critical role of IRF-5 in the development of T helper 1 responses to Leishmania donovani infection

• Published in: PLoS pathogens 2011-01, Vol.7 (1), p.e1001246-e1001246
• Main Authors: Paun, Andrea, Bankoti, Rashmi, Joshi, Trupti, Pitha, Paula M, Stäger, Simona
• Format: Article
• Language: English
• Subjects: Animals; Development and progression; Disease Models, Animal; Female; Gene Expression; Granuloma - immunology; Granuloma - parasitology; Granuloma - pathology; HEK293 Cells - enzymology; Host-Parasite Interactions; Humans; Immune response; Immune system; Immunology/Immune Response; Immunology/Immunity to Infections; Immunology/Innate Immunity; Inbreeding; Infections; Infectious Diseases/Neglected Tropical Diseases; Infectious Diseases/Protozoal Infections; Interferon; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - physiology; Leishmania donovani; Leishmania donovani - immunology; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral - genetics; Leishmaniasis, Visceral - immunology; Leishmaniasis, Visceral - metabolism; Liver - immunology; Liver - parasitology; Liver - pathology; Luciferases - genetics; Luciferases - metabolism; Lymphocytes; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Parasites; Parasitic diseases; Physiological aspects; Proteins; Regulation; RNA, Messenger - metabolism; Spleen - immunology; Spleen - parasitology; Spleen - pathology; Th1 Cells - immunology; Th1 Cells - metabolism; Toll-like receptors; Transfection; Vector-borne diseases; Viral infections
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1001246

The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5⁻/⁻ mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression.