{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:00:19Z","timestamp":1782280819809,"version":"3.54.5"},"posted":{"date-parts":[[2025,11,19]]},"group-title":"Microbiology","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The capacity of\n                  <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                  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\n                  <jats:italic>A. fumigatus<\/jats:italic>\n                  stress resistance, host cell interactions, and virulence. A \u0394\n                  <jats:italic>hosA<\/jats:italic>\n                  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\n                  <jats:italic>in vitro<\/jats:italic>\n                  . In a corticosteroid-immunosuppressed mouse model of invasive aspergillosis, mice infected with the \u0394\n                  <jats:italic>hosA<\/jats:italic>\n                  mutant survived significantly longer than those infected with the wild-type strain, despite having similar pulmonary fungal burden. The \u0394\n                  <jats:italic>hosA<\/jats:italic>\n                  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\n                  <jats:italic>A. fumigatus<\/jats:italic>\n                  interactions with host cells and virulence during invasive pulmonary aspergillosis.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    Epigenetic modifications in\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    can 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 several\n                    <jats:italic>Aspergillus<\/jats:italic>\n                    species, but its function in\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    was previously unknown. We found that deletion of\n                    <jats:italic>hosA<\/jats:italic>\n                    increased susceptibility to intracellular, but not extracellular, oxidative stress. The \u0394\n                    <jats:italic>hosA<\/jats:italic>\n                    mutant 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.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.19.689210","type":"posted-content","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T17:55:12Z","timestamp":1763574912000},"source":"Crossref","is-referenced-by-count":0,"title":["The HosA histone deacetylase regulates stress resistance, host cell interactions, and virulence in\n                  <i>Aspergillus fumigatus<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3804-9535","authenticated-orcid":false,"given":"Hong","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Vo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjoy","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quynh T.","family":"Phan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5202-6304","authenticated-orcid":false,"given":"Jianfeng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1683-2015","authenticated-orcid":false,"given":"Vincent M.","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Stamnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7163-1120","authenticated-orcid":false,"given":"W. Scott","family":"Moye-Rowley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7278-3700","authenticated-orcid":false,"given":"Scott G.","family":"Filler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025112201050698000_2025.11.19.689210v1.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000200"},{"key":"2025112201050698000_2025.11.19.689210v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/152.1.33"},{"key":"2025112201050698000_2025.11.19.689210v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s004380050767"},{"key":"2025112201050698000_2025.11.19.689210v1.4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041242"},{"key":"2025112201050698000_2025.11.19.689210v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05726.x"},{"key":"2025112201050698000_2025.11.19.689210v1.6","doi-asserted-by":"crossref","first-page":"e1009235","DOI":"10.1371\/journal.ppat.1009235","article-title":"Determining Aspergillus fumigatus transcription factor expression and function during invasion of the mammalian lung","volume":"17","year":"2021","journal-title":"PLoS Pathog"},{"key":"2025112201050698000_2025.11.19.689210v1.7","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.9.5193-5203.2004"},{"key":"2025112201050698000_2025.11.19.689210v1.8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008551"},{"key":"2025112201050698000_2025.11.19.689210v1.9","doi-asserted-by":"crossref","unstructured":"Li X , Pan L , Wang B , Pan L . 2019. 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Antifungal activity of sustainable histone deacetylase inhibitors against planktonic cells and biofilms of Candida spp. and Cryptococcus neoformans . Med Mycol 61.","DOI":"10.1093\/mmy\/myad073"},{"key":"2025112201050698000_2025.11.19.689210v1.31","doi-asserted-by":"crossref","first-page":"128132","DOI":"10.1016\/j.micres.2025.128132","article-title":"Histone deacetylase Hos1 promotes the homeostasis of Candida albicans cell wall and membrane and its specific inhibitor has an antifungal activity in vivo","volume":"296","year":"2025","journal-title":"Microbiol Res"},{"key":"2025112201050698000_2025.11.19.689210v1.32","doi-asserted-by":"crossref","unstructured":"Min K , Ichikawa Y , Woolford CA , Mitchell AP. 2016. 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