1. Immune responses to C. difficile infection (CDI) (Funded: Merck, CIHR)
Our laboratory examines the role of T-cell immunity in CDI and how it correlates with initial infection, relapsing infection, and response to fecal microbial therapy (FMT or “stool transplant”). We are also examining the role of adaptive immunity and toxin neutralization in mouse models of CDI.
2. Development of cellular therapy for inflammatory bowel disease (IBD) (Funded: Crohn’s and Colitis Canada)
Using a novel technology known as the chimeric antigen receptor (CAR), we are developing regulatory T cells specific to bacterial flagellin, a key antigen in IBD. The goal is to obtain regulatory T cells from patients with IBD, introduce the flagellin-CAR, and infuse them back into the patient, where they will home to the intestinal immune tissues and suppress inflammation. We are also examining the potential role of type-1 regulatory T cells (Tr1) in cellular therapy.
3. Role of stress signals in intestinal immunity
We have shown that intestinal epithelial immune responses to bacterial products like flagellin are modulated by exposure to stress or danger signals. We are currently using human-derived intestinal organoids (enteroids) to model these responses, and understand the link between epithelial stress responses and development of abnormal anti-commensal adaptive immune responses to drive inflammation in IBD.
4. Modulation of TLR5 signalling in taxonomically diverse flagellins
We are examining the molecular mechanisms of flagellin/TLR5 interaction and inflammatory signaling, based on the observation that some flagellins that are targets of robust antibody and T cell responses yet poor TLR5 agonists.
5. Measurement of T cell responses to antibiotics in patients with delayed-type hypersensitivity reactions
Using a novel FACS-based T cell activation assay, we are measuring antibiotic-specific T cell responses in patients presenting with allergic reactions to antibiotics (rashes, kidney injury, etc.) to develop a clinically useful test that can determine safety to rechallenge in the future.
U The Role of Flagellin in Anti-Bacterial Inflammatory Responses
We study the inflammatory response to the flagellin from enteroaggregative E. coli (EAEC), an emerging diarrheal pathogen. Bacterial flagellins are recognized by Toll-like receptor 5 (TLR5), leading to NF-kB activation, chemokine release, T-cell activation, and other inflammatory phenotypes. Our work is currently focused on several key projects:
- Studies of molecular inflammatory signalling in response to bacterial flagellin acting through Toll-like receptor 5 (TLR5).
- Identifying the role of flagellin/TLR5 interaction in the abnormal inflammatory responses that characterize Crohn’s disease
- Studies of flagellin-reactive effector and regulatory populations of T cells in the human gut in inflammatory bowel disease
- Pathogenic mechanisms of infectious diarrhea due to enteroaggregative E. coli
1. Fecal microbial therapy for recurrent CDI
I participate in several studies examining the benefits of different routes and types of FMT material for the treatment of recurrent CDI. As the leading provider of FMT in BC, I have performed the procedure on over 150 patients as part of different clinical trials.
2. Novel CDI prevention and treatment I have participated as a site investigator on trials of CDI vaccines and new therapeutic agents
My main area of focus is intestinal infections, including CDI and travel-related diarrhea, particularly in difficult clinical situations, such as CDI in the setting of IBD. I am also certified in Tropical Medicine and see general infectious disease consultations in both inpatient and outpatient settings. As an immunology researcher, I am also very interested in infections complicating biologic therapies for autoimmune diseases.
Ivison SM, Graham NR, Bernales CQ, Kifayet A, Ng N, Shobab LA, Steiner TS. Protein kinase D interaction with TLR5 is required for inflammatory signaling in response to bacterial flagellin. J Immunol. 2007 May 1;178(9):5735-43.
Ivison SM, Khan MA, Graham NR, Bernales CQ, Kaleem A, Tirling CO, Cherkasov A, Steiner TS. A phosphorylation site in the Toll-like receptor 5 TIR domain is required for inflammatory signalling in response to flagellin. Biochem Biophys Res Commun. 2007 Jan 26;352(4):936-41.
Steiner TS. How flagellin and toll-like receptor 5 contribute to enteric infection. Infect Immun. 2007 Feb;75(2):545-52.
Steiner TS, Samie A, Guerrant RL. Infectious diarrhea: new pathogens and new challenges in developed and developing areas. Clin Infect Dis. 2006 Aug 15;43(4):408-10.
Khan MA, Kang J, Steiner TS. Enteroaggregative Escherichia coli flagellin-induced interleukin-8 secretion requires Toll-like receptor 5-dependent p38 MAP kinase activation. Immunology. 2004 Aug;112(4):651-60.
Donnelly MA, Steiner TS. Two nonadjacent regions in enteroaggregative Escherichia coli flagellin are required for activation of toll-like receptor 5. J Biol Chem. 2002 Oct 25;277(43):40456-61.
Guerrant RL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV,
Hennessy T, Griffin PM, DuPont H, Sack RB, Tarr P, Neill M, Nachamkin I, Reller LB, Osterholm MT, Bennish ML, Pickering LK; Infectious Diseases Society of America. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001 Feb 1;32(3):331-51.
Steiner TS, Nataro JP, Poteet-Smith CE, Smith JA, Guerrant RL. Enteroaggregative Escherichia coli expresses a novel flagellin that causes IL-8 release from intestinal epithelial cells. J Clin Invest. 2000 Jun;105(12):1769-77.