Deployment, consequences and utility of bacterial effectors. (360G-Wellcome-104556_Z_14_Z)

The Type VI secretion system (T6SS) is a key weapon in the virulence and competitiveness of many bacteria, including important human pathogens; however its mechanisms and roles are not well understood. T6SSs can be anti-eukaryotic, used to target eukaryotic cells as direct virulence factors, or anti-bacterial, used to efficiently kill rival bacterial cells and provide a competitive advantage (indirect virulence factors). T6SSs inject multiple effector proteins directly into target cells. Several classes of anti-bacterial effectors have recently been reported, with apparently many more yet to be described, whereas dedicated anti-eukaryotic effectors remain to be identified. We aim to answer key questions regarding how secretion of diverse effector proteins by the T6SS is achieved, how it contributes to the success of bacterial pathogens, and how this understanding might be exploited. We will integrate a variety of molecular and cell biology approaches to elucidate how the T6SS recruits and secretes multiple, diverse effector proteins in a flexible yet specific manner. A newly-identified anti-eukaryotic T6SS will be studied in order to identify its secreted effectors and relate their function to the virulence role of the system. We will also examine the acquisition of new T6-effectors by a bacterium, including the ease of functional transmission and the quantitative contribution of both the T6SS itself and the newly-acquired effectors to its competitive fitness. During the stud y we will experimentally identify multiple T6SS-secreted effector proteins and determine the molecular function of novel examples. Finally, we will explore the potential for therapeutic exploitation of our findings.