Decay-Accelerating Factor 1 Deficiency Exacerbates Leptospiral-Induced Murine Chronic Nephritis and Renal Fibrosis

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.

Eyedrop Inoculation Causes Sublethal Leptospirosis in Mice

“…Intraperitoneal infectious doses ranging from 10 3 to 10 9 have been used in mice aged 3 to 14 weeks (27)(28)(29)(30). In our study, we determined that ϳ10 8 cells of L. interrogans serovar Copenhageni were needed to establish infection consistently in 100% of the C3H/HeJ mice at 10 weeks of age.…”

Lethality of leptospirosis depends on sex: male hamsters succumb to infection with lower doses of pathogenic Leptospira

“…Production of pro-inflammatory chemokines reflects an immune response that may promote further renal damage. Fibroblast activation marker (collagen1 A1, ColA1) and iNOS are known to play important roles in Leptospira-induced interstitial nephritis (39), (40) and kidney fibrosis (41) in mice. The quantification of mRNA transcripts in kidney of non-survivor hamsters showed up-regulation of ColA1, but not iNOS, which was absent.…”

First observation of neutrophil extracellular traps in human leptospirosis

“…Search for leptospiral antigen in lung tissues using antibodies against Leptospira interrogans was intended using an immunohistochemical procedure that have been described before. [7] 2.2 NETs detection As regarding NETs detection, a few modifications for a better visualization in paraffin embedded tissues using a immunofluorescence (IF) technique were recently published [5] and applied in this case. Rabbit polyclonal against human neutrophil elastase (NE) (Calbiochem-Merk Millipore -Darmstad, Germany), or citrulinated histone 3 (H3cit) (Santa Cruz, Ca, USA), followed by anti species antibody labeled with different fluorochromes were used.…”