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

Abstract

The capacity ofto 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 HosA instress resistance, host cell interactions, and virulence. A Δmutant 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 a corticosteroid-immunosuppressed mouse model of invasive aspergillosis, mice infected with the Δmutant survived significantly longer than those infected with the wild-type strain, despite having similar pulmonary fungal burden. The Δmutant 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 governsinteractions with host cells and virulence during invasive pulmonary aspergillosis.IMPORTANCEEpigenetic modifications incan be induced by environmental changes and stresses such as those induced by interaction with host cells. HosA, a class I histone deacetylase, has been shown to play a key role in regulating secondary metabolism in severalspecies, but its function inwas previously unknown. We found that deletion ofincreased susceptibility to intracellular, but not extracellular, oxidative stress. The Δmutant also exhibited significantly reduced pulmonary epithelial cell invasion and host cell damage, as well as attenuated virulence in immunosuppressed mice. Together, these findings indicate that HosA functions as a key epigenetic regulator that governs stress resistance, secondary metabolism, and fungal-host interactions. Defining the functions of HosA could provide critical insight into the epigenetic mechanisms that control fungal pathogenicity and may reveal a potential therapeutic target for invasive aspergillosis.