Many bacterial pathogens attempt to adhere to or invade intestinal epithelial cells (IECs), often using virulence factors that manipulate cytosolic signaling pathways in the IEC. However, IECs are able to survey their cytosol by using innate immune sensors in the inflammasome family. We have shown that inflammasomes can detect the activity of bacterial secretion systems by detecting aberrant translocation of bacterial flagellin, rod, and needle proteins. Inflammasomes have largely been studied in macrophages, where active caspase-1 was first shown to cleave pro-IL-1? and pro-IL-18 to their mature and released forms. Caspase-1 was recently shown to cleave a third protein, gasdermin D, which forms a pore in the plasma membrane that causes programmed lytic cell death, or pyroptosis. The function of caspase-1 in other cell types is now beginning to be studied, and these may be slightly different from its function in macrophages. In this regard, in IECs inflammasomes were recently shown to drive exfoliation of the compromised IEC, ejecting it into the gut lumen. Caspase-1 is the founding member of the larger caspase family. Caspases are normally considered as either apoptotic or inflammatory, however in recent years many interactions across classes have been demonstrated. Here we examine how IECs are defended by caspase-1, but also that other normally apoptotic caspases are also involved in exfoliation. We will study the innate immune inflammasome sensors that drive exfoliation during bacterial infection, and also how different innate immune cells coordinate their activities to promote IEC exfoliation.

Public Health Relevance

Bacteria are a frequent cause of gastrointestinal infection. The immune system fights back against bacterial infection in the gut by sensing the infecting pathogens when they perturb the intestinal epithelial cells that line the gut. This grant studies how intestinal epithelial cells detach as a defense against gut infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI139304-03
Application #
9912096
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2018-05-11
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599