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.

cCampylobacter jejuni is a helix-shaped enteric bacterial pathogen and a common cause of gastroenteritis. We recently developed a mouse model for this human pathogen utilizing the SIGIRR-deficient mouse strain, which exhibits significant intestinal inflammation in response to intestinal C. jejuni infection. In the current study, this mouse model was used to define whether C. jejuni's characteristic helical shape plays a role in its ability to colonize and elicit inflammation in the mouse intestine. Mice were infected with the previously characterized straight-rod ⌬pgp1 and ⌬pgp2 mutant strains, along with a newly characterized curved-rod ⌬1228 mutant strain. We also compared the resultant infections and pathology to those elicited by the helix-shaped wild-type C. jejuni and complemented strains. Despite displaying wild-type colonization of the intestinal lumen, the straightrod ⌬pgp1 and ⌬pgp2 mutants were essentially nonpathogenic, while all strains with a curved or helical shape retained their expected virulence. Furthermore, analysis of C. jejuni localization within the ceca of infected mice determined that the primary difference between the rod-shaped, nonpathogenic mutants and the helix-shaped, pathogenic strains was the ability to colonize intestinal crypts. Rod-shaped mutants appeared unable to colonize intestinal crypts due to an inability to pass through the intestinal mucus layer to directly contact the epithelium. Together, these results support a critical role for C. jejuni's helical morphology in enabling it to traverse and colonize the mucus-filled intestinal crypts of their host, a necessary step required to trigger intestinal inflammation in response to C. jejuni. Campylobacter jejuni is a Gram-negative, microaerophilic bacterium and a common cause of infectious gastroenteritis. It possesses bipolar flagella and is highly motile. One of its defining characteristics is its helical shape, from which its name is derived. Although some rod-shaped Campylobacter species have been described (such as C. hominis, C. showae, C. ureolyticus, C. concisus, and C. gracilis [1, 2]), and rod-shaped variants of C. jejuni have been isolated (3), these appear to be the exception, with the helical shape being the standard morphology for C. jejuni as well as a number of related species among the epsilonproteobacteria, such as the gastric pathogen Helicobacter pylori.The shape of a bacterial cell is maintained by its peptidoglycan (PG) layer (4). While many bacteria have a relatively simple coccoid or bacillus shape, modification of the PG layer can allow for the creation of more complex cell shapes such as the helix (5, 6). PG-modifying enzymes have been described as being responsible for generating the helical shape of H. pylori (Csd1, Csd2, Csd3/ HdpA, Csd4, and Csd6) (7-13) and C. jejuni (Pgp1 and Pgp2) (14, 15). Pgp1 and Pgp2 are homologs of H. pylori Csd4 and Csd6, respectively. In addition, homologs of the H. pylori Csd1 and Csd3/HdpA proteins have also been identified in C. jejuni, and characterization is ongoi...