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 indirect role of IRF-5 in the regulation of iNOS expression.
Highlights
The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis (VL), a chronic life threatening disease if untreated
As toll like receptors (TLRs) have been implicated in the recognition of Leishmania parasites [5,6,7,20,21,22,23], we first wanted to assess whether Interferon Regulatory Factor 5 (IRF-5) was at all involved in the generation of protective immunity against L. donovani
As the development of IFNcproducing CD4+ T cell in L. donovani infected mice was shown to depend upon IL-12 production by conventional CD11chi dendritic cells (DC), we examined whether Interferon Regulatory Factors (IRFs)-5 deficient DC were able to produce IL-12 in vivo following L. donovani infection
Summary
The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis (VL), a chronic life threatening disease if untreated. While the spleen stays chronically infected, infection in the liver is self-resolving within 68 weeks due to the development of a Th1-dominated granulomatous response, which is characterized by high IFNc production. This response is induced by IL-12 secreted by dendritic cells (DC) [2,3,4] and is crucial for parasite control and disease resolution in the liver, together with TNFa production and expression of inducible nitric oxide synthase (iNOS) by macrophages [1]. Since Leishmania parasites reside in the phagolysosomes of the host cells, other endosomally localized TLRs, such as TLR 7 and 8 could be involved in the recognition of this pathogen [10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
