How Gram-positive pathogens impair E-cadherin functions

The epithelium covers important organs within the human body and efficiently protects from bacterial infections. However, many pathogens developed fascinating mechanisms to overcome this epithelial barrier. In our previous research we identified the bacterial enzyme HtrA that cleaves the cell adhesion molecule and signaling protein E-cadherin on infected host cells. HtrA-mediated E-cadherin cleavage plays a central role in the efficient disruption of the epithelial lining and promotes bacterial infection. However, HtrA varies in structure, activity and function in different bacterial species. In the proposed project, the applicants will investigate a novel undescribed activation mechanism of HtrA in Listeria monocytogenes and Staphylococcus aureus, which are responsible for severe infectious diseases. Novel substrates and HtrA inhibitors will be identified using cutting-edge technical and cellular approaches. A series of advanced and innovative cell models will be generated to analyze the functional repertoire of HtrA and its impact on bacterial adherence and invasion, and ultimately the disruption and crossing of the epithelial barrier. Demonstrating the importance of HtrA in bacterial infection processes, our project will uncover new mechanisms of pathogen-host interactions, which might lead to novel strategies to combat bacterial infections.

The epithelium covers important organs within the human body and efficiently protects from bacterial infections. However, many pathogens developed fascinating mechanisms to overcome this epithelial barrier. Our previous research identified the bacterial enzyme HtrA, which cleaves cell surface proteins on infected host cells and thus weakens the epithelial barrier, allowing the bacteria to penetrate deeper regions of the tissue. HtrA-mediated E-cadherin cleavage plays a central role in the efficient disruption of the epithelial lining and promotes bacterial infection. However, HtrA varies in structure, activity, and function in different bacterial Gram-positive and Gram-negative species. In this project, a fragmentation cascade of autoproteolytic active HtrA expressed by Listeria monocytogenes and Staphylococcus aureus was characterized. Novel HtrA substrates from epithelial cells and specific HtrA inhibitors were identified using cutting-edge technical and advanced cellular approaches. Demonstrating the importance of HtrA in bacterial infection processes, the project uncovered new mechanisms of pathogen-host interactions, which might lead to novel strategies to combat bacterial infections.