We co-exist in harmony with huge numbers of bacteria, many within our own gastrointestinal (GI) tracts. On occasion, however, particularly virulent bacteria called pathogens (Salmonella, EHEC O157:H7) infect our intestines and cause severe, even fatal, disease. To fight infections, our immune system must recognize these bacteria as harmful and trigger a protective immune response. Some individuals appear highly susceptible to infections, perhaps because their immune systems are unable to recognize or effectively deal with the bacteria. Inappropriate recognition of pathogens may also contribute to chronic diseases of the GI tract such as Crohn's disease and other inflammatory bowel diseases (IBD). We believe that in IBD an individual’s immune system mistakes harmless bacteria for pathogens and attacks them, causing chronic inflammation. Using immunological and microbiological techniques, we’re learning how our immune systems recognize bacteria in the GI tract. We’re also identifying the factors that can provide resistance or susceptibility to intestinal infections, and exploring the mechanisms underlying the dysfunctional pathogen recognition that can trigger chronic IBD.

Role of intestinal epithelial cells in controlling bacterial infections
Many intestinal bacterial pathogens – including enterohemorrhagic E. coli (EHEC O157:H7), the causative agent of the water poisoning in Walkerton, Ontario – infect the epithelial cells that line our intestines. Our recent work has shown that during such infections, epithelial cells are activated to produce a variety of anti-microbial molecules. Moreover, in vitro studies indicate that EHEC and related pathogens may inject bacterial proteins into infected epithelial cells in order to reduce the production of anti-microbial enzymes by epithelial cells. We are currently identifying the bacterial effector proteins as well as the mechanisms involved in this process.

Mechanisms underlying host susceptibility to enteric pathogens
Additional studies have identified several related mouse strains that are highly susceptible to Citrobacter rodentium, a mouse adapted version of EHEC. Susceptible animals show evidence of inflammation similar to that seen in human inflammatory bowel diseases. Using in vivo imaging, we have identified specific sites in the intestine where susceptibility first manifests, as well as the bacterial virulence factors needed to colonize these sites. We are currently identifying the genes underlying the susceptibility defect in these mice, since a similar defect may predispose humans to increased
 
Role of dendritic cells in mucosal infection and inflammation
Dendritic cells are the sentinel immune cells of the body, trafficking to mucosal sites where they acquire antigen to ultimately present to naïve T cells. Recent work in several laboratories suggests that some bacterial pathogens may infect dendritic cells at intestinal mucosal surfaces, using these cells to shuttle across the intestinal epithelial barrier to cause a systemic infection. We are currently examining the role of dendritic cells in enabling the colonization and infection of the GI tract by invasive bacteria (Salmonella) and non-invasive bacteria (EHEC), as well as their role in causing intestinal inflammation in models of IBD. Our work has also revealed that dendritic cells may actually play an active role in host defense, expressing various anti-microbial effectors. We are currently studying the mechanisms of dendritic cell mediated anti-microbial activity both in vitro and in vivo. A better understanding of the role of dendritic cells in GI inflammation may provide useful targets for improved vaccination against bacterial infections as well as provide therapeutic targets for IBD.

Vallance B.A., Gunawan M.I., Hewlett B., Bercik P., Van Kampen C., Galeazzi F., Sime P.J., Gauldie J., and Collins S.M. TGF- b 1 gene transfer to the mouse colon leads to intestinal fibrosis. Am. J. Physiol. (Gastrointest. Liver Physiol.), 289(7): G116-G128, 2005.

Coburn B., Li Y., Owen D., Vallance B.A., and Finlay B.B. Salmonella typhimurium pathogenicity island-2 is necessary for complete virulence in a mouse model of infectious enterocolitis. Infect. & Immun., 73(6): 3219-3227, 2005.

Hardwidge P.R., Deng W., Vallance B.A., Rodriquez-Escudero I. , Cid V.J., Molina M., and Finlay B.B. Modulation of host cytoskeleton function by the enteropathogenic Escherichia coli and Citrobacter rodentium effector protein EspG. Infect. & Immun., 73(5): 2586-2594, 2005.

Vallance B.A., Khan M.A., Deng W., Gruenheid S., and Finlay B.B. Modeling enteropathogenic and enterohemorrhagic E. coli infections and disease. Drug Disc. Today: Disease Models, 1(1): 73-79, 2004.

Vallance B.A., Dijkstra G., Qiu B.S., van der Waiij L.A. , van Goor H., Jansen P.L.M., Mashimo H., and Collins S.M. The relative contributions of nitric oxide synthase (NOS) isoforms to experimental colitis; endothelial derived NOS maintains mucosal integrity. Am. J. Physiol. (Gastrointest. Liver Physiol.)., 287(10): G865-G874, 2004.

Vazquez-Torres A., Vallance B.A., Bergman M.A., Finlay B.B., Cookson, B.T., Jones-Carson J., and Fang F.C. Toll-like receptor 4 dependence of innate and adaptive immunity to Salmonella: Importance of the kupffer cell network. J. Immunol., 172: 6202-6208, 2004.

Deng W., Puente J.L., Gruenheid S., Li Y., Vallance B.A., Vazquez A.V., Barba J., Ibarra J.A., O’Donnell P., Metalnikov P., Ashman K., Lee S., Goode D., Pawson T., and Finlay B.B. Dissecting virulence: Systematic and functional analysis of a pathogenicity island. Proc. Natl. Acad. Sci. USA., 101(10): 3597-3602, 2004.

Vallance B.A., Deng W., Jacobson K., and Finlay B.B. Host susceptibility to the attaching/effacing bacterial pathogen Citrobacter rodentium. Infect. & Immun., 71(6): 3443-3453, 2003.

Deng W., Vallance B.A., Li Y., Puente J.L., and Finlay B.B. Citrobacter rodentium’s translocated intimin receptor (Tir) is a virulence factor necessary for nucleating actin, intestinal colonization and colonic hyperplasia in mice. Mol. Microbiol., 48(1): 95-115, 2003.

Vallance B.A., Deng W., De Grado M., Chan C., Jacobson K., and Finlay B.B. Modulation of inducible nitric oxide synthase (iNOS) expression by the attaching/effacing bacterial pathogen Citrobacter rodentium in mice. Infect. & Immun., 70(11): 6424-6435, 2002.

CIHR Operating Grant – Project: "Defining SIGIRR's role in epithelial homeostasis and host defense during infectious colitis," 2013-2018

Canada Research Chair in Pediatric Gastroenterology (Tier II) – 2004-2009

Michael Smith Foundation for Health Research Scholar – 2004-2009

CHILD Foundation Research Scholar – 2003-ongoing

Dr. Mohammed Rumi – Postdoctoral fellow

Dr. Mohammed Khan – Graduate student

Mr. Kirk Bergstrom – Graduate student

Ms. Yanet Valdez – Graduate student

Ms. Caixia Ma – Research technician

Ms. Tina Huang – Research assistant