Mechanisms and impact of antifungal and dual-purpose effectors delivered by the Type VI secretion system

Microorganisms live in polymicrobial communities shaped by competitive interactions between their members. These interactions are key determinants of human microbiota composition and health. Many bacteria use Type VI secretion systems (T6SSs) to deliver antibacterial effectors (toxins) into competitor bacterial cells. We revealed previously that T6SSs also deploy specific antifungal effectors against fungal competitors. Subsequent work has shown that T6SS-mediated antifungal activity is widespread, that antifungal effectors display novel antifungal biology, and that some function as ‘dual-purpose’ effectors which also target other kingdoms. However, few antifungal effectors have been characterised and large knowledge gaps remain regarding delivery, spectrum-of-activity and real-life-impact. Here, we will use our cross-disciplinary expertise to elucidate the mechanisms and impact of antifungal and dual-purpose T6SS effectors, from molecular detail to complex microbial communities. Specifically, we will: expand the repertoire of antifungal and dual-purpose T6SS effectors and determine the spectrum-of-T6SS-activity against fungal and other eukaryotic microbes; define the mode-of-action and determinants of fungal compatibility for these effectors; and determine potential contributions of antifungal T6SSs and effectors to complex polymicrobial communities and future translational applications. Fungal pathogens represent a critical global-healthcare challenge. Elucidating how T6SSs operate as biological antifungal weapons and shape health-relevant microbial communities should inform future antifungal strategies.