Ryan Gaudet, Ph.D.

Assistant Professor of Microbiology & Immunology
Ph.D., University of Toronto

Anti-pathogen effector mechanisms, innate immunity, tissue-specific responses

Research

Encoded within the human genome is an arsenal of antimicrobial effectors that safeguard individual cells during infection. These restriction factors are not constitutively expressed but are part of elaborate and inducible self-defense programs that are mobilized in response to stimulation by immune cytokines like interferon. Though many effectors are synonymous with phagocytic cells like macrophages, it is now clear that analogous antimicrobial machineries exist in non-immune cells, and their tactical deployment is integral to establishing pathogen resistance in tissues – the sites of infection. Our lab seeks to understand the molecular mechanisms that underpin the ability of immune cytokines to transform seemingly vulnerable tissue cells into potent effectors of immune system.

We are interested in the following questions:

1) What effector proteins protect which cell-types, from what pathogens?
2) How do these proteins work inside cells?
3) How does their activation affect the core functions of tissues in which they are deployed?
4) What are the pathophysiological consequences of their erroneous regulation?

 We are using high-throughput genetic screens, genetically defined bacterial, protozoa and viral pathogens that replicate inside human cells, and inbred mouse models to begin answering these questions. We have a particular interest in functionally annotating the hundreds of orphan interferon-stimulated gene (ISG) encoded effectors that dominate transcriptional signatures of human tissues during infection, under certain physiological conditions, or during pro-inflammatory and autoimmune disease. As a member of the Human Tissue Immunity and Disease Initiative, we are conducting high dimensional profiling and functional studies of interferon- activated native human tissues, a previously intractable task. By analyzing multiple organs from donors across all ages of life, our goal is to create a functional, anatomical, and temporal map that outlines the battery of ISG-encoded effector proteins that control susceptibility and resistance to infection in non-lymphoid tissues like the lung, gut, skin and brain.

We are looking for curious, passionate, and collaborative researchers (postdocs, graduate students, medical students, undergrads, and technicians) to join our team. To inquire, please email Dr. Gaudet with a cover letter describing interest and CV.

Please see our lab website for more information about research and team members.

Selected Publications

1. R.G. Gaudet, S. Zhu, A. Halder, B.H. Kim, C.J. Bradfield, S. Huang, D. Xu, A. Mamiñska, T.N. Nguyen, M. Lazarou, E. Karatekin, K. Gupta and J.D. MacMicking. (2021) A human apolipoprotein L with detergent-like activity kills intracellular pathogens. Science 373: eabf8113 PMID: 34437126.

2. M. Abdel-Nour, L.A. Carneiro, J. Downey, J. Tsalikis, A. Outlioua, D. Prescott, L.S. Da Costa, E.S. Hovingh, A. Farahvash, R.G. Gaudet, R. Molinaro, R. Dalen C Lau, F.C. Azimi, N.K. Escalante, J.E. Lee, S.D. Gray-Owen, J.J. Chen, D.J. Philpott, D. Arnoult and S.E. Girardin. (2019) The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling. Science 365: eaaw4144.

3. T.R. O’Meara, K. Duah, C.X. Guo, M. Maxson, R.G. Gaudet, K. Koselny, M. Wellington, M. Powers, J. MacAlpine, M.J. O’Meara, A. Veir, S. Grinstein, S.M. Noble, D. Krysan, S.D. Gray-Owen and L.E. Cowen. (2018) High-throughput screening identifies genes required for Candida albicans induction of macrophage pyroptosis. mBio 9: e01581-18.

4. A. Gall, R.G. Gaudet, S.D. Gray-Owen and N. Salma. (2017) TIFA signaling in gastric epithelial cells initiates the cag-T4SS-dependent innate immune response to Helicobacter pylori infection. mBio 15: e01168-17.

5. R.G. Gaudet, C.X. Guo, R. Molinaro, J.R. Rohde, H. Kottwitz, A.S. Dangeard, C. Arriemerlou, S.E. Girardin and S.D. Gray-Owen. (2017) Innate recognition of intracellular bacterial growth is driven by the TIFA-dependent cytosolic surveillance pathway. Cell Reports 19: 1418-1430.

6. R.G. Gaudet, C.J. Bradfield and J.D. MacMicking. (2016) Evolution of cell-autonomous effector mechanisms in macrophages versus non-immune cells. Microbiology Spectrum 4 doi: 10.1128/microbiolspec.MCHD-0050-2016.

7. R.G. Gaudet and S.D. Gray-Owen. (2016) Heptose sounds the alarm: Innate recognition of a bacterial sugar stimulates immunity. PLoS Pathogens 129: e1005807 doi:10.1371/journal.ppat.1005807.

8. R.G. Gaudet, A. Sintsova, C.M. Buckwalter, N. Leung, J. Li, A. Cox, A. Cochrane, J. Moffat and S.D. Gray-Owen. (2015) Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity. Science 348: 1251-1255.

9. R.M. Malott, B. Keller, R.G. Gaudet, S. McCaw, C. Lai, W. Belaire, J. Hobbs, F. St. Michael, A. Cox, T. Moraes and S.D. Gray-Owen. (2013) Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression. Proc. Natl. Acad. Sci. U.S.A. 110: 10234–10239.

10. R.G. Gaudet, F. Breden, F. Plummer and J.D. Berry. (2011) Molecular characterization of the cervical and systemic B-cell repertoire: Unique, yet overlapping immune compartments of an HIV-1 resistant individual. mAbs 3: 1-11.

11. J.D. Berry and R.G. Gaudet. (2011) Antibodies in infectious diseases, polyclonals, monoclonals and niche biotechnology. New Biotechnology 28: 489-501.