critical role of irf-5 in the development of t helper 1 responses to leishmania donovani infectionirf-5在发展的关键作用辅助t 1对杜氏利什曼虫感染的反应.pdfVIP

Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection 1¤ 2 2 1,3 ¨ 2 Andrea Paun , Rashmi Bankoti , Trupti Joshi , Paula M. Pitha *, Simona Stager * 1 Sidney Kimmel Comprehensive Center, The Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America, 3 Biology Department, The Johns Hopkins University, Baltimore, Maryland, United States of America Abstract 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