Mast Cells Limit Systemic Bacterial Dissemination but Not Colitis in Response toCitrobacter rodentium

Abstract

Enteropathogenic Escherichia coli and enterohemorrhagic E. coli cause an inflammatory colitis in human patients characterized by neutrophil infiltration, proinflammatory cytokine expression, and crypt hyperplasia. Citrobacter rodentium causes a similar colitis in mice and serves as a model for enteropathogenic E. coli infection in humans. C. rodentium induces systemic T-cell-dependent antibody production that facilitates clearance of the bacteria and protects the host from reinfection. The role of innate immune cells in infectious colitis, however, is less well understood. In this study, we have determined the role of mast cells in the inflammatory response and disease induced by C. rodentium. Mice deficient in mast cells exhibit more severe colonic histopathology and have a higher mortality rate following infection with C. rodentium than do wild-type animals. Despite unimpaired neutrophil recruitment and lymphocyte activation, mast cell-deficient mice have a disseminated infection evident in crucial organ systems that contributes to sepsis. Importantly, mast cells also have the capacity to directly kill C. rodentium. Together, these results suggest that mast cells protect the host from systemic infection by reducing the bacterial load and preventing dissemination of the bacterium from the colon.Enteric pathogens such as enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) attach to and colonize the host gastrointestinal tract and cause weight loss, diarrhea, crypt hyperplasia, and transient colitis. EPEC is a major contaminant in food and water sources in developing countries and causes significant increases in morbidity and mortality, primarily among children. EHEC contaminates food and water sources in industrialized nations and causes both diarrhea and hemolytic-uremic syndrome. A related pathogen, Citrobacter rodentium, has only about 50% of its genes in common with EPEC and EHEC but nevertheless induces disease in rodents that is virtually identical to that caused by EPEC and EHEC in humans. C. rodentium infection in mice is widely used as an animal model of pathogenic E. coli infection in humans (7, 9, 10, 18-21, 34, 42, 43, 45-47).EPEC, EHEC, and C. rodentium all induce a characteristic lesion in the intestine of the host that is characterized by intimate attachment to the host intestinal epithelial cells and effacement of microvilli. Such attaching and effacing (A/E) lesions result from translocation of virulence proteins from the bacterium into the host cell (13,22,23,26). These factors induce formation of membranous protrusions, called pedestals, beneath the bacterium, and anchor the bacterium to the host cell (reviewed in reference 36). Pedestal formation is required for subsequent disease (31, 37). EPEC, EHEC, and C. rodentium all contain a 35-kb pathogenicity island called LEE (locus of enterocyte effacement) that encodes ϳ41 virulence factors that are essential for the formation of A/E lesions and for disease. The virulence factors from the LEE loci of EPEC, EHEC, and C. r...

Gamma Interferon Produced by Antigen-Specific CD4+T Cells Regulates the Mucosal Immune Responses toCitrobacter rodentiumInfection

“…1C, the serum anti-OVA IgG levels were significantly elevated in mice infected with OVA-C. rodentium at 7, 14, and 28 days after infection. The presence of C. rodentium in the feces of mice infected with OVA-C. rodentium at 7, 14, and 28 days after infection was confirmed by PCR of bacterial colonies using Tir-specific primers (26) (Fig. 1D and E).…”

Infection of Mast Cells with Live Streptococci Causes a Toll-Like Receptor 2- and Cell-Cell Contact-Dependent Cytokine and Chemokine Response

“…Since then, a large number of reports have shown similar findings, i.e., that MC deficiency results in a markedly elevated susceptibility to a host of different bacterial insults. For example, MC-deficient mice are much more sensitive to infection caused by Citrobacter rodentium (62), Helicobacter felis (63), Listeria monocytogenes (17), Pseudomonas aeruginosa (50), and invasive group A streptococci (10) than are corresponding WT animals.…”

Mast cells are crucial for early inflammation, migration of Langerhans cells, and CTL responses following topical application of TLR7 ligand in mice

“…Evidence further accumulates that mast cells are implicated in host defense against a still increasing range of clinically relevant bacterial infections. [3][4][5] Furthermore, mast cells are also thought to participate in response to viruses, but this is less understood and deserves further research. 5,6 With respect to IgEindependent activation, both rodent and human mast cells were found to express a variety of Toll-like receptors, some of which are expressed only on certain mast cell subsets.…”