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- Title
Leptospira Interrogans Induces Fibrosis in the Mouse Kidney through Inos-Dependent, TLR- and NLR-Independent Signaling Pathways.
- Authors
Fanton d'Andon, Martine; Quellard, Nathalie; Fernandez, Béatrice; Ratet, Gwenn; Lacroix-Lamandé, Sonia; Vandewalle, Alain; Boneca, Ivo G.; Goujon, Jean-Michel; Werts, Catherine
- Abstract
Background: Leptospira (L.) interrogans are bacteria responsible for a worldwide reemerging zoonosis. Rodents carry L. interrogans asymptomatically in their kidneys and excrete bacteria in the urine, contaminating the environment. Humans get infected through skin contact and develop a mild or severe leptospirosis that may lead to renal failure and fibrosis. L. interrogans provoke an interstitial nephritis, but the induction of fibrosis caused by L. interrogans has not been studied in murine models. Innate immune receptors from the TLR and NLR families have recently been shown to play a role in the development and progression of tissue fibrosis in the lung, liver and kidneys under different pathophysiological situations. We recently showed that TLR2, TLR4, and NLRP3 receptors were crucial in the defense against leptospirosis. Moreover, infection of a human cell line with L. interrogans was shown to induce TLR2-dependent production of fibronectin, a component of the extracellular matrix. Therefore, we thought to assess the presence of renal fibrosis in L. interrogans infected mice and to analyze the contribution of some innate immune pathways in this process. Methodology/principal findings: Here, we characterized by immunohistochemical studies and quantitative real-time PCR, a model of Leptospira-infected C57BL/6J mice, with chronic carriage of L. interrogans inducing mild renal fibrosis. Using various strains of transgenic mice, we determined that the renal infiltrates of T cells and, unexpectedly, TLR and NLR receptors, are not required to generate Leptospira-induced renal fibrosis. We also show that the iNOS enzyme, known to play a role in Leptospira-induced interstitial nephritis, also plays a role in the induction of renal fibrosis. Conclusion/significance: To our knowledge, this work provides the first experimental murine model of sustained renal fibrosis induced by a chronic bacterial infection that may be peculiar, since it does not rely on TLR or NLR receptors. This model may prove useful to test future therapeutic strategies to combat Leptospira-induced renal lesions. Author Summary: Leptospirosis is a bacterial disease transmitted by asymptomatic rodents to humans. The symptoms may be mild, or severe with kidney failure. Renal fibrosis, occurring during inflammatory situations, is characterized by the pathological accumulation of extra-cellular matrix components and can compromise the kidney functions of patients with leptospirosis. Recent research revealed that both innate and adaptive immune responses are involved in the establishment of fibrosis, in several organs and in different pathophysiological situations. In the present study, we characterized a mouse model of chronic infection with Leptospira that provokes mild renal fibrosis. We show that fibrogenesis requires the presence of live Leptospira in the kidney and that B and T cells from the adaptive immune response do not participate in the induction of renal fibrosis. Unexpectedly, we also found that innate immune receptors, TLRs and NLRs, are not involved in the Leptospira-induced fibrosis. Finally, we show that the enzyme responsible for NO production, iNOS, known to participate in renal inflammatory lesions induced by Leptospira, is also involved in renal fibrosis. Our work provides a novel mouse model to study fibrosis occurring due to leptospirosis.
- Subjects
RENAL fibrosis; LEPTOSPIRA interrogans; CELLULAR signal transduction; EXTRACELLULAR matrix; PULMONARY fibrosis; KIDNEY failure; INTERSTITIAL nephritis
- Publication
PLoS Neglected Tropical Diseases, 2014, Vol 8, Issue 1, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0002664