A new model of self-resolving leptospirosis in mice infected with a strain of Leptospira interrogans serovar Autumnalis harboring LPS signaling only through TLR4

• Published in: Emerging microbes & infections 2017-05, Vol.6 (1), p.1-12
• Main Authors: Xia, Bili, Sun, Le, Fan, Xia, Xiao, Haihan, Zhu, Yongzhang, Qin, Jinhong, Cai, Chengsong, Zhao, Wei, Chang, Yung-Fu, Zhang, Yan, Guo, Xiaokui, He, Ping
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Load; Disease Models, Animal; Jaundice - microbiology; Kidney - microbiology; Kidney - pathology; Leptospira interrogans serovar autumnalis - physiology; leptospires; Leptospirosis; Leptospirosis - immunology; Leptospirosis - metabolism; Leptospirosis - microbiology; lipopolysaccharide; Lipopolysaccharides - metabolism; Liver - microbiology; Liver - pathology; Lung - microbiology; Lung - pathology; Macrophages - immunology; Mice; Mice, Inbred C57BL; mouse model; Nitric Oxide Synthase Type II - biosynthesis; Original; Pathogenesis; Rodents; Signal Transduction; Studies; TLR4; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism
• ISSN: 2222-1751; 2222-1751
• DOI: 10.1038/emi.2017.16

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. Emerging Microbes & Infections (2017) 6, e30 doi: 10.1038/emi.2017.16 ; published online 24 May 2017