Intestinal epithelial cells act as a first barrier against pathogen intrusion. One effective way to prevent traversal of invading bacteria to the underlying tissue is inflammasome-induced epithelial cell extrusion of infected epithelial cells, a process we and others described recently. Inflammasomes are cytosolic sensors of pathogenic behavior, allowing cells to distinguish between harmless commensals and pathogens, which try to access the cell. After an inflammasome gets activated, cleavage of Caspases is triggered, which leads to a cascade of downstream events such as lytic cell death and cytokine release. We still don’t understand many aspects of this fascinating cell biological process, especially in epithelial cells. Using stem cell derived organoid in vitro as well as in vivo models of gastrointestinal pathogen infection for our research, we are currently aiming to answer the following questions:
- What are the signals downstream of inflammasome activation that lead to epithelial cell extrusion? (Collins Medical Trust funded)
- Are certain pathogens capable of suppressing this response with effector molecules? What are the consequences?
- What is the role of inflammasomes in tuft cells, a specialized type of epithelial cell? (NIH funded R01)
As shown recently, NLRC4-deficient mice are highly susceptible to infection with Shigella flexneri- a pathogen that causes significant mortality through diarrheal disease in humans. We are collaborating with Najit Technologies to use our in vivo mouse Shigella infection model to test vaccine candidates against Shigella.
If you think these are exciting questions to study, or want to discuss the many other project ideas we (or you?) have, contact us.