Constitutive activation of TORC1 signaling attenuates virulence in the cross-kingdom fungal pathogen Fusarium oxysporum

Abstract

ABSTRACTThe filamentous fungus Fusarium oxysporum causes vascular wilt disease in a wide range of plant species and opportunistic infections in humans. Previous work suggested that invasive growth in this pathogen is controlled by environmental cues such as pH and nutrient status. Here we investigated the role of Target Of Rapamycin Complex 1 (TORC1), a global regulator of eukaryotic cell growth and development. Inactivation of the negative regulator Tuberous Sclerosis Complex 2 (Tsc2), but not constitutive activation of the positive regulator Gtr1, in F. oxysporum resulted in inappropriate activation of TORC1 signaling under nutrient limiting conditions. The tsc2Δ mutants showed reduced colony growth on minimal medium with different nitrogen sources and increased sensitivity to cell wall or high temperature stress. Furthermore, these mutants were impaired in invasive hyphal growth across cellophane membranes and exhibited a marked decrease in virulence, both on tomato plants and on the invertebrate animal host Galleria mellonella. Importantly, invasive hyphal growth in tsc2Δ strains was rescued by rapamycin-mediated inhibition of TORC1. Collectively, these results reveal a key role of TORC1 signaling in development and pathogenicity of F. oxysporum and suggest new potential targets for controlling fungal infections.AUTHOR SUMMARYFilamentous fungal pathogens cause devastating losses in agriculture and lethal infections in humans. A prerequisite of fungal infection is invasive hyphal growth, a process that is exquisitely controlled by environmental cues including nutrients and host signals. Here we examined the role of TOR complex 1 (TORC1), a conserved pathway that regulates cell growth in response to nutrient status. We show that deregulation of TORC1 signaling impairs pathogenicity in Fusarium oxysporum, a cross-kingdom fungal pathogen that attacks more than 150 different crops as well as immunocompromised humans. Inactivation of Tsc2, a negative regulator of TORC1, led to constitutive TORC1 activation, reduced growth under nutrient-limiting conditions and increased sensitivity to cell wall stress. Importantly, tsc2Δ mutants were impaired in invasive hyphal growth and in virulence on plant and animal hosts. Our results support a conserved role of TORC1 as a negative regulator of pathogenicity-related functions and reveal new leads for antifungal drug discovery.