A Novel Mouse Model of Campylobacter jejuni Gastroenteritis Reveals Key Pro-inflammatory and Tissue Protective Roles for Toll-like Receptor Signaling during Infection

PLoS Pathogens

Xiaoxia Li¹  Erin C. Gaynor²  Jenny Vermeulen²  Hong Yang³  Stuart E. Turvey³  Shauna M. Crowley⁴  Yuliya Badayeva⁴  Bruce A. Vallance⁴  Jenna Ries⁴  Martin Stahl⁴  Ho Pan Sham⁴ 

[1] Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America;Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada;Department of Pediatrics, British Columbia Children's Hospital and Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada;Division of Gastroenterology, British Columbia Children's Hospital, the Child and Family Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada

关键词: Mouse models;    Inflammation;    Campylobacter jejuni;    Gastrointestinal tract;    Toll-like receptors;    Vancomycin;    Gastroenteritis;    Colon;   

DOI  :  10.1371/journal.ppat.1004264

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Campylobacter jejuni is a major source of foodborne illness in the developed world, and a common cause of clinical gastroenteritis. Exactly how C. jejuni colonizes its host's intestines and causes disease is poorly understood. Although it causes severe diarrhea and gastroenteritis in humans, C. jejuni typically dwells as a commensal microbe within the intestines of most animals, including birds, where its colonization is asymptomatic. Pretreatment of C57BL/6 mice with the antibiotic vancomycin facilitated intestinal C. jejuni colonization, albeit with minimal pathology. In contrast, vancomycin pretreatment of mice deficient in SIGIRR (Sigirr−/−), a negative regulator of MyD88-dependent signaling led to heavy and widespread C. jejuni colonization, accompanied by severe gastroenteritis involving strongly elevated transcription of Th1/Th17 cytokines. C. jejuni heavily colonized the cecal and colonic crypts of Sigirr−/− mice, adhering to, as well as invading intestinal epithelial cells. This infectivity was dependent on established C. jejuni pathogenicity factors, capsular polysaccharides (kpsM) and motility/flagella (flaA). We also explored the basis for the inflammatory response elicited by C. jejuni in Sigirr−/− mice, focusing on the roles played by Toll-like receptors (TLR) 2 and 4, as these innate receptors were strongly stimulated by C. jejuni. Despite heavy colonization, Tlr4−/−/Sigirr−/− mice were largely unresponsive to infection by C. jejuni, whereas Tlr2−/−/Sigirr−/− mice developed exaggerated inflammation and pathology. This indicates that TLR4 signaling underlies the majority of the enteritis seen in this model, whereas TLR2 signaling had a protective role, acting to promote mucosal integrity. Furthermore, we found that loss of the C. jejuni capsule led to increased TLR4 activation and exaggerated inflammation and gastroenteritis. Together, these results validate the use of Sigirr−/− mice as an exciting and relevant animal model for studying the pathogenesis and innate immune responses to C. jejuni.

【 授权许可】

CC BY