Many species of bacteria use a contractile nanomachine known as the Type VI secretion system (T6SS) to deliver a wide range of toxic ‘effector’ proteins directly into neighbouring cells. The T6SS plays a key role in the virulence and competitiveness of diverse Gram-negative bacteria, including important human, animal and plant pathogens. In some cases the T6SS can be used to directly attack host cells, as a classical virulence factor. However the primary role of the T6SS is believed to be during inter-bacterial competition, when bacteria use the T6SS to deliver anti-bacterial effectors into other bacterial cells, efficiently killing or disabling their rivals. Additionally, we have recently discovered that bacteria can also use T6SS-delivered effectors against microbial fungi, including important fungal pathogens. Anti-microbial T6SSs thus provide a competitive mechanism to allow pathogens to proliferate in polymicrobial infection sites or environmental reservoirs and ultimately cause disease. Understanding T6SS-mediated effector delivery and the lethal consequences of these effectors on targeted cells therefore offers the potential to uncover new ways to kill or inhibit bacterial and fungal pathogens, as well as fundamental insights into the dynamics of polymicrobial communities more broadly.
In the Coulthurst group, we study the roles and regulation of the T6SS, the mechanisms of effector delivery, and the nature and mode-of-action of T6SS-dependent effector proteins. We utilise a wide range of molecular, genetic and cellular approaches and focus on representative examples of Gram-negative bacterial pathogens. In this project, we will investigate how the same T6SS secretion system can be used to target both bacterial and fungal competitor cells, considering aspects of the regulation of expression and assembly of the T6SS itself as well as the regulation and mode-of-action of specific effector proteins. In an inter-disciplinary study, we will combine, as required, microbial cell biology, genetics and biochemical approaches (Coulthurst and Stanley-Wall groups) with advanced microscopy and image analysis, including single-molecule imaging (Rickman group, ESRIC). We aim to gain new insight into whether and how deployment of the T6SS is adapted to particular target microbes or whether specificity is dictated by effector modes of action. Ultimately we hope that the findings of this project may contribute to the development of new anti-microbial strategies of relevance to health and agriculture. The student will gain experience in state-of-the-art molecular and imaging techniques as well as a strong grounding in microbiology and opportunities to engage with the international research community and the general public.
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