Abstract
Leptospirosis is a global zoonosis caused by pathogenic Leptospira, which can colonize the proximal renal tubules and persist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type and Daf1−/− mice, which have an enhanced host response, with a virulent Leptospira interrogans strain at 14 days post-infection, its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found that Leptospira interrogans can induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in the absence of mortality. In contrast, Daf1−/− mice showed acute mortality, with a higher bacterial burden. At the chronic stage, Daf1−/− mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times than the wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 and IL-13, with similar levels of α-smooth muscle actin, galectin-3, TGF-β1, IL-17, IFN-γ, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf1−/− mice was accompanied by high expression of α-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-γ, similar levels of TGF-β1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link between Leptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1.
Highlights
Renal fibrosis is a reliable predictor of prognosis, a major determinant of renal insufficiency and a common final outcome of almost all progressive chronic kidney diseases (CKD) [1,2]
Leptospira interrogans induces discrete to moderate nephritis in mice In order to investigate whether Leptospira interrogans, serovar Copenhageni (LIC), was able to induce murine renal inflammation, and to study how an enhanced host response could impact in the disease, C57BL/6J wild-type (WT) and Daf12/2 mice of 3–4 weeks of age were infected with 106 bacteria and groups of five animals were euthanized and necropsied at 14 and 90 days postinfection
In order to study if anti-leptospiral antibody production and enhanced complement activation contributed to kidney damage, we analyzed the membrane attack complex (MAC) tissue distribution by IHC and observed minimal MAC presence in Daf12/2 infected mice at 90 dpi (Figure 4 C–H)
Summary
Renal fibrosis is a reliable predictor of prognosis, a major determinant of renal insufficiency and a common final outcome of almost all progressive chronic kidney diseases (CKD) [1,2]. Leptospirosis is usually a biphasic disease with an early bacteremic phase during which leptospires are disseminated rapidly throughout the body during the first 7–10 days of infection This is followed by a leptospiruric phase during which specific antibodies arise in parallel with the disappearance of the bacteria from the blood and most organs with the exception of the kidneys, where it can persist for long periods of time [8]. It has been reported that Daf12/2 mice are more susceptible to complement-mediated inflammatory injury and have significantly enhanced T-cell responses to active immunization This phenotype is characterized by hypersecretion of interferon (IFN)-c and IL-2 as well as down-regulation of the inhibitory cytokine IL-10 during antigen restimulation of lymphocytes in vitro [19]. We report the establishment of a murine model of chronic leptospirosis followed by fibrosis in wild-type and Daf12/2 mice
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