PMID- 28536433
OWN - NLM
STAT- MEDLINE
DCOM- 20171218
LR  - 20181113
IS  - 2222-1751 (Electronic)
IS  - 2222-1751 (Linking)
VI  - 6
IP  - 5
DP  - 2017 May 24
TI  - A new model of self-resolving leptospirosis in mice infected with a strain of 
      Leptospira interrogans serovar Autumnalis harboring LPS signaling only through 
      TLR4.
PG  - e36
LID - 10.1038/emi.2017.16 [doi]
AB  - 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.
FAU - Xia, Bili
AU  - Xia B
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
AD  - Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.
FAU - Sun, Le
AU  - Sun L
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
FAU - Fan, Xia
AU  - Fan X
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
FAU - Xiao, Haihan
AU  - Xiao H
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
FAU - Zhu, Yongzhang
AU  - Zhu Y
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
FAU - Qin, Jinhong
AU  - Qin J
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
FAU - Cai, Chengsong
AU  - Cai C
AD  - Department of Laboratory Medicine, Affiliated Hospital of Hangzhou Normal 
      University, Hangzhou 311121, Zhejiang Province, China.
FAU - Zhao, Wei
AU  - Zhao W
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
FAU - Chang, Yung-Fu
AU  - Chang YF
AUID- ORCID: 0000-0001-8902-3089
AD  - Department of Population Medicine and Diagnostic Sciences, College of Veterinary 
      Medicine, Cornell University, Ithaca, NY 14853, USA.
FAU - Zhang, Yan
AU  - Zhang Y
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
FAU - Guo, Xiaokui
AU  - Guo X
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
FAU - He, Ping
AU  - He P
AD  - Department of Microbiology and Immunology, Institutes of Medical Science, 
      Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
LA  - eng
PT  - Journal Article
DEP - 20170524
PL  - United States
TA  - Emerg Microbes Infect
JT  - Emerging microbes & infections
JID - 101594885
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Toll-Like Receptor 4)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Bacterial Load
MH  - *Disease Models, Animal
MH  - Jaundice/microbiology
MH  - Kidney/microbiology/pathology
MH  - Leptospira interrogans serovar autumnalis/physiology
MH  - *Leptospirosis/immunology/metabolism/microbiology
MH  - Lipopolysaccharides/*metabolism
MH  - Liver/microbiology/pathology
MH  - Lung/microbiology/pathology
MH  - Macrophages/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nitric Oxide Synthase Type II/biosynthesis
MH  - Signal Transduction
MH  - Toll-Like Receptor 4/genetics/*immunology/*metabolism
PMC - PMC5520481
EDAT- 2017/05/26 06:00
MHDA- 2017/12/19 06:00
PMCR- 2017/05/01
CRDT- 2017/05/25 06:00
PHST- 2016/11/17 00:00 [received]
PHST- 2017/01/19 00:00 [revised]
PHST- 2017/02/13 00:00 [accepted]
PHST- 2017/05/25 06:00 [entrez]
PHST- 2017/05/26 06:00 [pubmed]
PHST- 2017/12/19 06:00 [medline]
PHST- 2017/05/01 00:00 [pmc-release]
AID - emi201716 [pii]
AID - 10.1038/emi.2017.16 [doi]
PST - epublish
SO  - Emerg Microbes Infect. 2017 May 24;6(5):e36. doi: 10.1038/emi.2017.16.