Outcome of infection of C57BL/6 IL-10(-/-) mice with Campylobacter jejuni strains is correlated with genome content of open reading frames up- and down-regulated in vivo.

Human Campylobacter jejuni infection can result in an asymptomatic carrier state, watery or bloody diarrhea, bacteremia, meningitis, or autoimmune neurological sequelae. Infection outcomes of C57BL/6 IL-10(-/-) mice orally infected with twenty-two phylogenetically diverse C. jejuni strains were evaluated to correlate colonization and disease phenotypes with genetic composition of the strains. Variation between strains was observed in colonization, timing of development of clinical signs, and occurrence of enteric lesions. Five pathotypes of C. jejuni in C57BL/6 IL-10(-/-) mice were delineated: little or no colonization, colonization without disease, colonization with enteritis, colonization with hemorrhagic enteritis, and colonization with neurological signs with or without enteritis. Virulence gene content of ten sequenced strains was compared in silico; virulence gene content of twelve additional strains was compared using a C. jejuni pan-genome microarray. Neither total nor virulence gene content predicted pathotype; nor was pathotype correlated with multilocus sequence type. Each strain was unique with regard to absences of known virulence-related loci and/or possession of point mutations and indels, including phase variation, in virulence-related genes. An experiment in C. jejuni 11168-infected germ-free mice showed that expression levels of ninety open reading frames (ORFs) were significantly up- or down-regulated in the mouse cecum at least two-fold compared to in vitro growth. Genomic content of these ninety C. jejuni 11168 ORFs was significantly correlated with the capacity to colonize and cause enteritis in C57BL/6 IL-10(-/-) mice. Differences in gene expression levels and patterns are thus an important determinant of pathotype in C. jejuni strains in this mouse model.

Genetic background of IL-10(-/-) mice alters host-pathogen interactions with Campylobacter jejuni and influences disease phenotype.

We hypothesized that particular genetic backgrounds enhance rates of colonization, increase severity of enteritis, and allow for extraintestinal spread when inbred IL-10(-/-) mice are infected with pathogenic C. jejuni. Campylobacter jejuni stably colonized C57BL/6 and NOD mice, while congenic strains lacking IL-10 developed typhlocolitis following colonization that mimicked human campylobacteriosis. However, IL-10 deficiency alone was not necessary for the presence of C. jejuni in extraintestinal sites. C3H/HeJ tlr4(-/-) mice that specifically express the Cdcs1 allele showed colonization and limited extraintestinal spread without enteritis implicating this interval in the clinical presentation of C. jejuni infection. Furthermore, when the IL-10 gene is inactivated as in C3Bir tlr4(-/-) IL-10(-/-) mice, enteritis and intensive extraintestinal spread were observed, suggesting that clinical presentations of C. jejuni infection are controlled by a complex interplay of factors. These data demonstrate that lack of IL-10 had a greater effect on C. jejuni induced colitis than other immune elements such as TLR4 (C3H/HeJ, C3Bir IL-10(-/-)), MHC H-2g7, diabetogenic genes, and CTLA-4 (NOD) and that host genetic background is in part responsible for disease phenotype. C3Bir IL-10(-/-) mice where Cdcs1 impairs gut barrier function provide a new murine model of C. jejuni and can serve as surrogates for immunocompromised patients with extraintestinal spread.

C57BL/6 and congenic interleukin-10-deficient mice can serve as models of Campylobacter jejuni colonization and enteritis.

Campylobacter jejuni is a globally distributed cause of human food-borne enteritis and has been linked to chronic joint and neurological diseases. We hypothesized that C. jejuni 11168 colonizes the gastrointestinal tract of both C57BL/6 mice and congenic C57BL/6 interleukin-10-deficient (IL-10(-/-)) mice and that C57BL/6 IL-10(-/-) mice experience C. jejuni 11168-mediated clinical signs and pathology. Individually housed mice were challenged orally with C. jejuni 11168, and the course of infection was monitored by clinical examination, bacterial culture, C. jejuni-specific PCR, gross pathology, histopathology, immunohistochemistry, and anti-C. jejuni-specific serology. Ceca of C. jejuni 11168-infected mice were colonized at high rates: ceca of 50/50 wild-type mice and 168/170 IL-10(-/-) mice were colonized. In a range from 2 to 35 days after infection with C. jejuni 11168, C57BL/6 IL-10(-/-) mice developed severe typhlocolitis best evaluated at the ileocecocolic junction. Rates of colonization and enteritis did not differ between male and female mice. A dose-response experiment showed that as little as 10(6) CFU produced significant disease and pathological lesions similar to responses seen in humans. Immunohistochemical staining demonstrated C. jejuni antigens within gastrointestinal tissues of infected mice. Significant anti-C. jejuni plasma immunoglobulin levels developed by day 28 after infection in both wild-type and IL-10-deficient animals; antibodies were predominantly T-helper-cell 1 (Th1)-associated subtypes. These results indicate that the colonization of the mouse gastrointestinal tract by C. jejuni 11168 is necessary but not sufficient for the development of enteritis and that C57BL/6 IL-10(-/-) mice can serve as models for the study of C. jejuni enteritis in humans.