MycoViralPath · The role of fungal viruses in shaping fungal pathogenesis and mammalian host responses

Fungal pathogens present a significant threat to global health. As eukaryotes, they share considerable homology with their hosts, necessitating the development of innovative, non-cross-reactive therapies. Mycoviruses, viruses of fungi, can transform fungal virulence. Yet, despite their ubiquity and importance, the underlying mechanisms driving mycoviral infection and their consequences on fungal pathogenesis remain understudied. Using a naturally mycovirus-infected Aspergillus fumigatus strain, a model human fungal pathogen, we found that the mycovirus bestows a survival benefit to the fungus under oxidative stress and in the murine lung. We posit that mycoviral pressure modulates fungal fitness and virulence, thereby shaping the fungal host repertoire and facilitating the emergence of new fungal diseases. The proposed research aims to elucidate the mycoviral, fungal and mammalian determinants governing fungal cell fate during infection. We will:1) determine the molecular details governing mycoviral impact on fungal fitness, virulence, and host adaptation, 2) identify fungal antiviral mechanisms, and 3) determine how mycoviral infection affects the mammalian antifungal response. This complex multipartite pathosystem (mycovirus-fungal host-mammalian host) is highly heterogenous and dynamic, and this diversity can trigger different infection outcomes. To this end, we have developed a suite of fluorescent probes of fungal and mycoviral infection and of fungal physiology that enable tracking of virus-fungus-host interactions at single-cell resolution, and assessment of the physiological state of phagocytosed fungi in the host tissue. We propose the first in vivo interaction map of a virus within a fungus within an animal in the context of in vivo infection. We anticipate that this work will fundamentally shift our paradigms of fungal pathogenesis, and lay the groundwork for the development of novel therapeutics that operate in an entirely unexploited target space.