A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene Network during Host Interactions

Abstract

Mucolares are an ancient group of fungi encompassing the causal agents for the lethal infection mucormycosis. The high lethality rates, the emerging character of this disease, and the broad antifungal resistance of its causal agents are mucormycosis features that are alarming clinicians and researchers. Thus, the research field around mucormycosis is currently focused on finding specific weaknesses and targets in Mucorales for developing new treatments. In this work, we tested the role of the <i>white-collar</i> genes family in the virulence potential of <i>Mucor lusitanicus</i>. Study of the three genes of this family, <i>mcwc-1a</i>, <i>mcwc-1b</i>, and <i>mcwc-1c</i>, resulted in a marked functional specialization, as only <i>mcwc-1a</i> was essential to maintain the virulence potential of <i>M. lusitanicus</i>. The traditional role of <i>wc-1</i> genes regulating light-dependent responses is a thoroughly studied field, whereas their role in virulence remains uncharacterized. In this work, we investigated the mechanism involving <i>mcwc-1a</i> in virulence from an integrated transcriptomic and functional approach during the host-pathogen interaction. Our results revealed <i>mcwc-1a</i> as a master regulator controlling an extensive gene network. Further dissection of this gene network clustering its components by type of regulation and functional criteria disclosed a multifunctional mechanism depending on diverse pathways. In the absence of phagocytic cells, <i>mcwc-1a</i> controlled pathways related to cell motility and the cytoskeleton that could be associated with the essential tropism during tissue invasion. After phagocytosis, several oxidative response pathways dependent on <i>mcwc-1a</i> were activated during the germination of <i>M. lusitanicus</i> spores inside phagocytic cells, which is the first stage of the infection. The third relevant group of genes involved in virulence and regulated by <i>mcwc-1a</i> belonged to the "unknown function," indicating that new and hidden pathways are involved in virulence. The unknown function category is especially pertinent in the study of mucormycosis, as it is highly enriched in specific fungal genes that represent the most promising targets for developing new antifungal compounds. These results unveil a complex multifunctional mechanism used by <i>wc-1</i> genes to regulate the pathogenic potential in Mucorales that could also apply to other fungal pathogens.