The HosA histone deacetylase regulates stress resistance, host cell interactions, and virulence in Aspergillus fumigatus

The capacity of Aspergillus fumigatus to cause invasive pulmonary aspergillosis depends on its ability to adapt to dynamic and stressful microenvironments within the host. Epigenetic regulation, including histone deacetylation, plays a critical role in fungal adaptation to stress. Here, we investigated the role of the class I histone deacetylase (HDAC) HosA in A. fumigatus stress resistance, host cell interactions, and virulence. A Δ hosA mutant had increased susceptibility to intracellular oxidant stress induced by menadione. It also had impaired capacity to invade and damage two pulmonary epithelial cell lines in vitro . In a corticosteroid-immunosuppressed mouse model of invasive aspergillosis, mice infected with the Δ hosA mutant survived significantly longer than those infected with the wild-type strain, despite having similar pulmonary fungal burden. The Δ hosA mutant also induced a weaker inflammatory response than the wild-type strain. Transcriptomic analysis revealed that HosA regulates genes involved in secondary metabolite biosynthesis and energy metabolism, functioning as both an activator and repressor of distinct gene sets. Collectively, these results indicate that HosA is a key epigenetic regulator that governs A. fumigatus interactions with host cells and virulence during invasive pulmonary aspergillosis.