Overview

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.

Publications

Indispensable functions of ABL and PDGF receptor kinases in epithelial adherence of attaching/effacing pathogens under physiological conditions
DOI: 10.1152/ajpcell.00013.2014
2014

Intestinal epithelium-specific MyD88 signaling impacts host susceptibility to infectious colitis by promoting protective goblet cell and antimicrobial responses
DOI: 10.1128/IAI.02045-14
2014

A Novel Mouse Model of Campylobacter jejuni Gastroenteritis Reveals Key Pro-inflammatory and Tissue Protective Roles for Toll-like Receptor Signaling during Infection
DOI: 10.1371/journal.ppat.1004264
2014

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen
DOI: 10.1172/JCI74428
2014

DNBS/TNBS colitis models: providing insights into inflammatory bowel disease and effects of dietary fat.
2014

CD4+ T cells drive goblet cell depletion during citrobacter rodentium infection
DOI: 10.1128/IAI.00655-13
2013

The mucin muc2 limits pathogen burdens and epithelial barrier dysfunction during salmonella enterica serovar typhimurium colitis
DOI: 10.1128/IAI.00854-13
2013

Requirement of epithelial integrin-linked kinase for facilitation of Citrobacter rodentium-induced colitis
DOI: 10.1186/1471-230X-13-137
2013

Activation of p38a in T cells regulates the intestinal host defense against attaching and effacing bacterial infections
DOI: 10.4049/jimmunol.1300908
2013

The Citrobacter rodentium mouse model: studying pathogen and host contributions to infectious colitis.
2013

SIGIRR, a Negative Regulator of TLR/IL-1R Signalling Promotes Microbiota Dependent Resistance to Colonization by Enteric Bacterial Pathogens
DOI: 10.1371/journal.ppat.1003539
2013

Resistin-like molecule a promotes pathogenic Th17 cell responses and bacterial-induced intestinal inflammation
DOI: 10.4049/jimmunol.1200706
2013

Bacterial stimulation of the TLR-MyD88 pathway modulates the homeostatic expression of ileal paneth cell a-defensins
DOI: 10.1159/000341630
2013

Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses
DOI: 10.1152/ajpgi.00320.2012
2012

MyD88 signaling promotes both mucosal homeostatic and fibrotic responses during Salmonella-induced colitis
DOI: 10.1152/ajpgi.00038.2012
2012

Regulated virulence controls the ability of a pathogen to compete with the gut microbiota
DOI: 10.1126/science.1222195
2012

Innate host responses to enteric bacterial pathogens: A balancing act between resistance and tolerance
DOI: 10.1111/j.1462-5822.2012.01750.x
2012

Attaching and effacing bacterial effector NleC suppresses epithelial inflammatory responses by inhibiting NF-¿B and p38 mitogen-activated protein kinase activation
DOI: 10.1128/IAI.05033-11
2011

Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression
DOI: 10.1152/ajpgi.00509.2010
2011

Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium-induced colitis
DOI: 10.1128/IAI.01104-10
2011

Citrobacter rodentium infection induces MyD88-dependent formation of ubiquitinated protein aggregates in the intestinal epithelium
DOI: 10.1159/000320644
2011

Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia
DOI: 10.1073/pnas.1006098107
2010

Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling
DOI: 10.1053/j.gastro.2010.06.057
2010

The pathogenic E. coli type III effector EspZ interacts with host CD98 and facilitates host cell prosurvival signalling
DOI: 10.1111/j.1462-5822.2010.01470.x
2010

Loss of single immunoglobulin interlukin-1 receptor-related molecule leads to enhanced colonic polyposis in Apcmin mice
DOI: 10.1053/j.gastro.2010.04.043
2010

Epithelial p38a controls immune cell recruitment in the colonic mucosa
DOI: 10.1371/journal.ppat.1000934
2010

Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa
DOI: 10.1371/journal.ppat.1000902
2010

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice
DOI: 10.1007/s00125-009-1626-y
2010

Control of Intestinal Homeostasis, Colitis, and Colitis-Associated Colorectal Cancer by the Inflammatory Caspases
DOI: 10.1016/j.immuni.2010.02.012
2010

The single IgG IL-1-related receptor controls TLR responses in differentiated human intestinal epithelial cells
DOI: 10.4049/jimmunol.0900021
2010

Innate immunity and microbes: Conversations with the gut leading to intestinal tissue repair and fibrosis
DOI: 10.2174/187152309789152002
2009

Salmonella infection of gallbladder epithelial cells drives local inflammation and injury in a model of acute typhoid fever
DOI: 10.1086/646608
2009

Vasoactive intestinal peptide ameliorates intestinal barrier disruption associated with Citrobacter rodentium-induced colitis
DOI: 10.1152/ajpgi.90551.2008
2009

Absence of stearoyl-CoA desaturase-1 does not promote DSS-induced acute colitis
DOI: 10.1016/j.bbalip.2009.08.001
2009

Nramp1 drives an accelerated inflammatory response during Salmonella -induced colitis in mice
DOI: 10.1111/j.1462-5822.2008.01258.x
2009

Nramp1 expression by dendritic cells modulates inflammatory responses during Salmonella Typhimurium infection
DOI: 10.1111/j.1462-5822.2008.01155.x
2008

Intestinal microbiota are transiently altered during Salmonella-induced gastroenteritis
DOI: 10.1586/17474124.2.4.525
2008

A novel secretion pathway of Salmonella enterica acts as an antivirulence modulator during salmonellosis
DOI: 10.1371/journal.ppat.1000036
2008

Flagellin-dependent and -independent inflammatory responses following infection by enteropathogenic Escherichia coli and Citrobacter rodentium
DOI: 10.1128/IAI.01141-07
2008

Chronic Enteric Salmonella Infection in Mice Leads to Severe and Persistent Intestinal Fibrosis
DOI: 10.1053/j.gastro.2007.12.043
2008

Aggregation via the red, dry, and rough morphotype is not a virulence adaptation in Salmonella enterica serovar typhimurium
DOI: 10.1128/IAI.01383-07
2008

Role of M-CSF-dependent macrophages in colitis is driven by the nature of the inflammatory stimulus
DOI: 10.1152/ajpgi.00453.2007
2008

MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacterrodentium-induced colitis
DOI: 10.1111/j.1462-5822.2007.01071.x
2008

Modulation of intestinal goblet cell function during infection by an attaching and effacing bacterial pathogen
DOI: 10.1128/IAI.00093-07
2008

Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis
DOI: 10.1111/j.1462-5822.2007.01052.x
2008

Saccharomyces boulardii ameliorates Citrobacter rodentium-induced colitis through actions on bacterial virulence factors
DOI: 10.1152/ajpgi.00173.2007
2007

The Toll-Interleukin-1 Receptor Member SIGIRR Regulates Colonic Epithelial Homeostasis, Inflammation, and Tumorigenesis
DOI: 10.1016/j.immuni.2007.02.012
2007

The adaptor Act1 is required for interleukin 17 - Dependent signaling associated with autoimmune and inflammatory disease
DOI: 10.1038/ni1439
2007

Genetic profiling of dendritic cells exposed to live- or ultraviolet-irradiated Chlamydia muridarum reveals marked differences in CXC chemokine profiles
DOI: 10.1111/j.1365-2567.2006.02488.x
2007

IL-4 gene transfer to the small bowel serosa leads to intestinal inflammation and smooth muscle hyperresponsiveness
DOI: 10.1152/ajpgi.00065.2006
2007

Citrobacter rodentium infection causes both mitochondrial dysfunction and intestinal epithelial barrier disruption in vivo: Role of mitochondrial associated protein (Map)
DOI: 10.1111/j.1462-5822.2006.00741.x
2006

Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice
DOI: 10.1128/IAI.74.5.2522-2536.2006
2006

Noradrenergic and cholinergic neural pathways mediate stress-induced reactivation of colitis in the rat
DOI: 10.1016/j.autneu.2005.12.002
2006

Salmonella pathogenicity island 2 is expressed prior to penetrating the intestine
DOI: 10.1371/journal.ppat.0010032
2005

Cloning vectors and fluorescent proteins can significantly inhibit Salmonella enterica virulence in both epithelial cells and macrophages: Implications for bacterial pathogenesis studies
DOI: 10.1128/IAI.73.10.7027-7031.2005
2005

TGF-ß1 gene transfer to the mouse colon leads to intestinal fibrosis
DOI: 10.1152/ajpgi.00051.2005
2005

Salmonella enterica serovar Typhimurium pathogenicity island 2 is necessary for complete virulence in a mouse model of infectious enterocolitis
DOI: 10.1128/IAI.73.6.3219-3227.2005
2005

Modulation of host cytoskeleton function by the enteropathogenic Escherichia coli and Citrobacter rodentium effector protein EspG
DOI: 10.1128/IAI.73.5.2586-2594.2005
2005

Myenteric plexus injury and apoptosis in experimental colitis
DOI: 10.1016/j.autneu.2004.10.006
2005

Relative contributions of NOS isoforms during experimental colitis: Endothelial-derived NOS maintains mucosal integrity
DOI: 10.1152/ajpgi.00187.2004
2004

Modeling enteropathogenic and enterohemorrhagic E. coli infections and disease
DOI: 10.1016/j.ddmod.2004.04.001
2004

SseK1 and SseK2 are novel translocated proteins of Salmonella enterica serovar Typhimurium
DOI: 10.1128/IAI.72.9.5115-5125.2004
2004

Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies
DOI: 10.1128/IAI.72.6.3315-3324.2004
2004

Toll-Like Receptor 4 Dependence of Innate and Adaptive Immunity to Salmonella: Importance of the Kupffer Cell Network
2004

Dissecting virulence: Systematic and functional analyses of a pathogenicity island
DOI: 10.1073/pnas.0400326101
2004

Salmonella type III effectors PipB and PipB2 are targeted to detergent-resistant microdomains on internal host cell membranes
DOI: 10.1046/j.1365-2958.2003.03598.x
2003

Host susceptibility to the attaching and effacing bacterial pathogen Citrobacter rodentium
DOI: 10.1128/IAI.71.6.3443-3453.2003
2003

SseA is required for translocation of Salmonella pathogenicity island-2 effectors into host cells
DOI: 10.1016/S1286-4579(03)00094-7
2003

Erratum: SopD2 is a novel type III secreted effector of Salmonella typhimurium that targets late endocytic compartments upon delivery into host cells (Traffic (2003) vol. 4 (1) (36-48))
2003

Citrobacter rodentium translocated intimin receptor (Tir) is an essential virulence factor needed for actin condensation, intestinal colonization and colonic hyperplasia in mice
DOI: 10.1046/j.1365-2958.2003.03429.x
2003

SopD2 is a novel type III secreted effector of Salmonella typhimurium that targets late endocytic compartments upon delivery into host cells
DOI: 10.1034/j.1600-0854.2003.40106.x
2003

Current progress in enteropathogenic and enterohemorrhagic Escherichia coli vaccines
DOI: 10.1586/14760584.1.4.483
2002

Host-pathogen interactions: Host resistance factor Nramp1 up-regulates the expression of Salmonella pathogenicity island-2 virulence genes
DOI: 10.1073/pnas.252415599
2002

Enteropathogenic and enterohemorrhagic Escherichia coli infections: Emerging themes in pathogenesis and prevention
2002

Modulation of inducible nitric oxide synthase expression by the attaching and effacing bacterial pathogen Citrobacter rodentium in infected mice
DOI: 10.1128/IAI.70.11.6424-6435.2002
2002

Salmonella effectors within a single pathogenicity island are differentially expressed and translocated by separate type III secretion systems
DOI: 10.1046/j.1365-2958.2002.02820.x
2002

Mice lacking T and B lymphocytes develop transient colitis and crypt hyperplasia yet suffer impaired bacterial clearance during Citrobacter rodentium infection
DOI: 10.1128/IAI.70.4.2070-2081.2002
2002

Neural change in Trichinella-infected mice is MHC II independent and involves M-CSF-derived macrophages
2001

IL-12 gene transfer alters gut physiology and host immunity in nematode-infected mice
2001

Enteropathogenic Escherichia coli infection induces expression of the early growth response factor by activating mitogen-activated protein kinase cascades in epithelial cells
DOI: 10.1128/IAI.69.10.6217-6224.2001
2001

Locus of enterocyte effacement from Citrobacter rodentium: Sequence analysis and evidence for horizontal transfer among attaching and effacing pathogens
DOI: 10.1128/IAI.69.10.6323-6335.2001
2001

Role of immunologic factors and cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in mice
2001

Mast cell-independent impairment of host defense and muscle contraction in T. spiralis-infected W/Wv mice
2001

Critical role for signal transducer and activator of transcription factor 6 in mediating intestinal muscle hypercontractility and worm expulsion in Trichinella spiralis-infected mice
DOI: 10.1128/IAI.69.2.838-844.2001
2001

Interleukin-5 deficient mice exhibit impaired host defence against challenge Trichinella spiralis infections
DOI: 10.1046/j.1365-3024.2000.00328.x
2000

Exploitation of host cells by enteropathogenic Escherichia coli
DOI: 10.1073/pnas.97.16.8799
2000

Inflammation-induced impairment of enteric nerve function in nematode- infected mice is macrophage dependent
2000

CD4 T cells and major histocompatibility complex class II expression influence worm expulsion and increased intestinal muscle contraction during Trichinella spiralis infection
1999

Putative inflammatory and immunological mechanisms in functional bowel disorders
DOI: 10.1053/bega.1999.0037
1999

The role of CD4+ lymphocytes in the susceptibility of mice to stress- induced reactivation of experimental colitis
DOI: 10.1038/13503
1999

IL-5 contributes to worm expulsion and muscle hypercontractility in a primary T. spiralis infection
1999

Stress, inflammation and the irritable bowel syndrome.
1999

Characterization of enteric functional changes evoked by in vivo anti- CD3 T cell activation
1999

T lymphocyte-dependent and -independent intestinal smooth muscle dysfunction in the T. spiralis-infected mouse
1998

T cell-mediated exocrine pancreatic damage in major histocompatibility complex class II-deficient mice
DOI: 10.1016/S0016-5085(98)70270-7
1998

The effect of nematode infection upon intestinal smooth muscle function
DOI: 10.1046/j.1365-3024.1998.00155.x
1998

Therapeutic effects of interleukin-4 gene transfer in experimental inflammatory bowel disease
1997

Persistent intestinal neuromuscular dysfunction after acute nematode infection in mice
DOI: 10.1053/gast.1997.v113.pm9322517
1997

Increased intestinal muscle contractility and worm expulsion in nematode-infected mice
1997

Role of smooth muscle in intestinal inflammation
1996

Research

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.

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 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.

Grants

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

NSERC Discovery Grant and Discovery Accelerator Supplement - Project: "Vitamin D - A Regulator of Host-Microbe Interactions in the Mammalian GI Tract?" (2013-2018)

Crohn’s and Colitis Foundation of Canada Discovery Research Grants - Project: "IBD: The result of an imbalance between inflammatory versus tissue protective innate signaling?" (2013-2016)

Honours & Awards

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

CH.I.L.D. Foundation Chair in Pediatric Gastroenterology – 2013-ongoing

Canadian Children Inflammatory Bowel Disease Network, CIHR and CH.I.L.D Foundation – 2013

Research Group Members

Joannie Allaire, Postdoctoral fellow
Else Bosman, Doctoral Student , Doctoral Student
Larissa Celiberto, Doctoral Student
Yan Chen, Student
Shauna Crowley, Doctoral Student , Doctoral Student
Emily Davies, Undergraduate Research Assistant
Mariana Diaz Gomez, Research Assistant
Franziska Graef, PhD Student
Emily Gubski, Summer Student
Mackenzie Gutierrez, Research Assistant
Vivian Han, Graduate Student, Graduate Student
Genelle Healey, Postdoctoral Fellow
Jingtian Huang, Research Assistant
Hyun-Jeong Ko, Visiting Associate Professor
Hong Ting Law, Postdoctoral Fellow
Julia Lee, Undergraduate Research Assistant
Qiaochu Liang, Graduate Student
Caixia Ma, Research Assistant / Research Technician
Navjit Moore, Summer Student
Clare Murphy, Research Assistant
Andy Sham, Project Manager
Kevin Tsai, Post Doctoral Fellow
Hyungjun Yang
Hongbing Yu, Research Associate
Qin Yu, Visiting Scientist