Girardin Lab

Dr Girardin did his undergraduate studies at the Ecole Normale Superieure (ENS), Paris, before his PhD at the Pasteur Institute (Paris) in the laboratory of Dr Moshe Yaniv. Stephen has been recruited in 2006 in the Dept of Laboratory Medicine and Pathobiology (LMP) at the University of Toronto, and was promoted to the rank of Professor in 2018. From 2007 to 2016, he held a CRC Tier 2 in Innate Immunity and Microbial Pathogenesis. He has been cross-appointed to the Dept of Immunology since 2015. Since 2021, he now holds a CRC Tier 1 in Intestinal Inflammation.

Early career (2001-5)- The field of innate immunity has received considerable attention in the past 20 years. During his post-doctoral studies at the Pasteur Institute (Paris, France) in the lab of Dr Philippe Sansonetti, Drs Stephen E. Girardin and Dana Philpott identified the first intracellular system of bacterial detection by showing that the Nod-like receptor (NLR), Nod1, senses the intracellular pathogen Shigella (Girardin et al. EMBO Reports, 2001). In 2003, they reported that the bacterial ligands detected by Nod1 (Girardin et al. Science 2003) and the related protein Nod2 (Girardin et al. JBC, 2003) are peptidoglycan-derived molecules. These findings have been instrumental for deepening our understanding of the pathogenesis of inflammatory bowel diseases (IBD), since mutations in NOD2 have been shown to confer the most significant risk to develop Crohn’s disease, a form of IBD.

(2006-Present)- At the University of Toronto, Dr Girardin has developed a research program aiming at establishing a strong footprint in the fields of innate immunity and intestinal inflammation. His research has been largely driven by the interest in understanding how the host copes with bacterial infection and by the motivation to understand how Crohn’s disease might be initiated by a breakdown in host-pathogen interactions at the level of the intestine. During the 2006-20 period, the Girardin lab has contributed 150 peer-reviewed articles, with lead authorship in journals such as Molecular Cell (2022), Science (2019), Nature Medicine (2011), Immunity (2014), Cell Host Microbe (2012, 2018), EMBO Journal (2013) and Cell Reports (2016, 2017, 2019). Together with the Philpott lab, the Girardin lab is exploring the molecular mechanisms that control intestinal inflammation and innate immunity to bacterial pathogens.

RESEARCH INTERESTS
Current research in the Girardin lab is focused on intestinal inflammation, induced either by infection with enteric pathogens or by dysregulation of the intestinal microbiota. The lab is also interested in two cellular processes that occur during infection: autophagy and protein misfolding stress. The lab’s pre-clinical research program uses cellular models, such as primary intestinal organoids, as well as animal models, and is directly relevant to human diseases, including Crohn’s disease (CD), colorectal cancer (CRC) and Parkinson’s disease (PD). It is comprised of five main axes:

Intestinal inflammation and CRC. It is well characterized that intestinal inflammation can fuel the progression of colorectal cancer. We are using animal models to study how the microbiota and members of the NLR family, in particular Nod1, Nod2 and Nlrp6, which detect specific microbial signatures in the intestine, control intestinal tumorigenesis.

NLRs and inflammatory pathways. We are using an integrated approach using epithelial cell lines, primary organoids and in vivo models of inflammation, to delineate the role played by innate immunity in the control of inflammatory pathways. Through this work, we have recently uncovered a new pathway that links cellular stress with innate immune signaling, the cytosolic unfolded protein response (cUPR) (Abdel-Nour et al. Science 2019).

Autophagy and bacterial infection. We have previously discovered that intracellular bacterial pathogens trigger a cellular stress response in infected host cells, characterized by the induction of amino acid starvation and mTOR inhibition, which unleashes the protective autophagic response. We are exploring new aspects of this complex response, in particular the role played by the transcription factors TFEB and TFE3, the master regulators of autophagic transcription regulation.

Cellular control of mitophagy. Mitochondrial dysfunction is a hallmark of bacterial infection. We have previously shown how the NLR proteins control mitochondrial homeostasis during infection. Through recently published work (Killackey et al. Molecular Cell 2022), we have now identified a new pathway of mitochondrial autophagy. We will explore how this pathway impacts on the intestinal epithelium during inflammation and how it impacts CRC.

Impact of the cUPR on proteostasis. Our research on the cUPR (see above) has potentially key implications for the understanding of the general mechanisms that control protein folding in the cell, which is deregulated in multiple neurodegenerative disorders, such as PD. We are using cellular and in vivo models to dissect the role of the cUPR in PD. This work additionally provides novel insights into the role played by inflammation in PD.

Paul Bi, PhD Candidate

I study the functions of HRI signaling pathway of the integrated stress response in normal intestinal epithelial cells and in diseased states. 

Adrienne Ranger, PhD Candidate

My project aims to delineate the role of intestinal epithelial inflammasomes using murine enteroids.

Marry Nissan, PhD Candidate

My project aims to elucidate the role of NOD1 and NOD2 in intestinal epithelial cells during bacterial infections.

Elaine Tam, Lab manager

I manage the general operation of the Philpott and Girardin labs. I also ensure that the germ free facility at DCM remains germ free and maintain multiple mouse lines.

Innes Magee, BSc Student

I am conducting research on the function of the cGAS-STING pathway in the context of interactions between host and microbes.

Previous Lab Members