Leptospirosis is an emerging worldwide zoonosis caused by pathogenic Leptospira spp. Our understanding of leptospirosis pathogenesis and host immune response remains limited, while mechanistic studies are hindered by a lack of proper animal models and immunological reagents. Here we established a murine model of acute and self-resolving leptospirosis by infecting 10-week-old C57BL/6 mice with Leptospira interrogans serovar Autumnalis strain 56606v, with characteristic manifestations including jaundice as well as subcutaneous and pulmonary bleeding, but no kidney lesions. We also verified that the lipopolysaccharide (LPS) of strain 56606v signaled through a TLR4-dependent pathway in murine bone marrow-derived macrophages (BMDMs), rather than the previously reported TLR2. In addition, upon infection with Leptospira strain 56606v, TLR4−/− C57BL/6 mice presented more severe jaundice and liver injury as well as higher bacterial loads than WT mice but milder pulmonary hemorrhaging. Molecular studies showed that leptospirosis-related bleeding coincides with the temporal kinetics of iNOS production, while jaundice and liver injury are probably due to insufficiently controlled bacterial loads in the liver. These results suggested that TLR4 is essential in mediating host leptospiral clearance and, to some extent, is associated with pulmonary and subcutaneous hemorrhage, probably through downstream inflammatory mediators, iNOS in particular. Overall, our murine model using immunocompetent mice might facilitate future studies into the pathogenesis of jaundice and bleeding in leptospirosis. Meanwhile, our study suggests the prospect of combining antibiotics and immunosuppressants in the treatment of severe leptospirosis presenting with pulmonary hemorrhage.
Human flora‐associated (HFA) piglet model was established to examine the effects of gut microbes from a different donor species on the intestinal morphology and mucosal immunity. Newborn germ‐free piglets, obtained by caesarean section, were orally inoculated with a human and a porcine faecal suspension, and artificially fed to establish a HFA group (n = 7) and pig flora‐associated (PFA) group (n = 7), respectively. All pigs were killed 6 weeks later. Tissue samples from duodenum, jejunum, ileum and colon were collected and studied by histochemistry and immunohistochemistry methods for intestinal morphological analyses and detection of immunocompetent cells. In summary, both groups of pigs performed well but HFA pigs had a somewhat better daily weight gain, and their jejunal villus height and crypt depth were significantly higher. In comparison with PFA pigs, the number of intraepithelial lymphocytes in jejunum was lower but the number of goblet cells containing neutral mucins was significantly increased in HFA pigs. No difference was observed in the number of mast cells. The areas of IgA producing cells and CD4+ T cells in the jejunum and IgG producing cells in the small intestine were significantly higher in HFA pigs. However, the areas of MHC class II expressing cells were significantly increased in the duodenum and colon. Additionally, the amount of Bifidobacteria spp. was significantly higher in HFA pigs. This study confirms that the composition of gut microbes differentially affects the host intestinal mucosal immunity and suggests that commensal bacteria have great effects on intestinal health and development.
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