{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T13:50:56Z","timestamp":1781877056352,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,17]]},"group-title":"Microbiology","reference-count":104,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Expression of a fungal-specific sub-telomeric gene,\n                  <jats:italic>hrmA<\/jats:italic>\n                  , in\n                  <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                  is important for a colony biofilm morphology termed H-MORPH, increased hypoxic fitness, and virulence in a murine model of invasive pulmonary aspergillosis (IPA). How expression of\n                  <jats:italic>hrmA<\/jats:italic>\n                  contributes to virulence and worse disease progression is ill-defined. Increased\n                  <jats:italic>hrmA<\/jats:italic>\n                  expression results in reduced attachment of the extracellular matrix (ECM) to the fungal cell wall resulting in decreased strain adherence. Fungal strains that are less adherent\n                  <jats:italic>in vitro<\/jats:italic>\n                  are typically less virulent as the ECM heteropolysaccharide galactosaminogalactan (GAG) aids in adhesion to host cells and confers protection from host responses. Here we report that the UDP-glucose 4-epimerase encoding gene required for GAG biosynthesis,\n                  <jats:italic>uge3<\/jats:italic>\n                  , is necessary for full virulence of the H-MORPH strain,\n                  <jats:italic>hrmA<\/jats:italic>\n                  <jats:sup>REV<\/jats:sup>\n                  (AF293::\n                  <jats:italic>hrmA<\/jats:italic>\n                  <jats:sup>D304G<\/jats:sup>\n                  ). In contrast, loss of\n                  <jats:italic>uge3<\/jats:italic>\n                  in the reference strain AF293 did not significantly impact virulence in the tested IPA murine model. Phenotypic, transcriptomic, and metabolic analyses of\n                  <jats:italic>uge3<\/jats:italic>\n                  loss in the respective strain backgrounds revealed a key role for Uge3 in central carbon metabolism in a strain specific context that promotes disease progression. These results complement the known role of Uge3 in GAG biosynthesis and highlight strain specific metabolic differences in pathogenic\n                  <jats:italic>A. fumigatus<\/jats:italic>\n                  strains.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                    forms adherent biofilms that contribute to its ability to persist and cause disease. However, significant strain diversity exists with regard to the morphology of\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    biofilms. A distinct colony morphotype associated with increased disease progression and low oxygen fitness, termed H-MORPH, was recently described. An additional defining feature of the H-MORPH biofilm morphotype is reduced\n                    <jats:italic>in vitro<\/jats:italic>\n                    adherence to surfaces. While reduced fungal strain adherence is most commonly associated with reductions in virulence, H-MORPH strains exhibit increased virulence relative to the well-studied N-MORPH reference strain AF293. Here we discover that the UDP-glucose 4-epimerase, Uge3, plays an important role in H-MORPH central carbon metabolism complementary to its role in production of the extracellular matrix polysaccharide galactosaminogalactan (GAG). In H-MORPH strains, this metabolic role for Uge3 becomes central to virulence. These data highlight\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    strain specific mechanisms of fungal carbon metabolism related to biofilm matrix production and fungal virulence.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.17.732805","type":"posted-content","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:55:29Z","timestamp":1781762129000},"source":"Crossref","is-referenced-by-count":0,"title":["A strain-specific metabolic role for the UDP-glucose 4-epimerase Uge3 in\n                  <i>Aspergillus fumigatus<\/i>\n                  virulence"],"prefix":"10.64898","author":[{"given":"Nicole E.","family":"Kordana","sequence":"first","affiliation":[{"name":"Geisel School of Medicine, Microbiology and Immunology Department, Dartmouth College, Hanover NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5853-3852","authenticated-orcid":false,"given":"Angus","family":"Johnson","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine, Microbiology and Immunology Department, Dartmouth College, Hanover NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4402-0295","authenticated-orcid":false,"given":"Charles","family":"Puerner","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine, Microbiology and Immunology Department, Dartmouth College, Hanover NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane T.","family":"Jones","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine, Microbiology and Immunology Department, Dartmouth College, Hanover NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7222-6987","authenticated-orcid":false,"given":"Caitlin H.","family":"Kowalski","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine, Microbiology and Immunology Department, Dartmouth College, Hanover NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine G.","family":"Quinn","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine, Microbiology and Immunology Department, Dartmouth College, Hanover NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko-wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine, Microbiology and Immunology Department, Dartmouth College, Hanover NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Le Mauff","sequence":"additional","affiliation":[{"name":"Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada"},{"name":"GlycoNet Integrated Services, Microbial Glycomic Node, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5503-5006","authenticated-orcid":false,"given":"Robert A.","family":"Cramer","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine, Microbiology and Immunology Department, Dartmouth College, Hanover NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061905552075000_2026.06.17.732805v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-54568-5"},{"key":"2026061905552075000_2026.06.17.732805v1.2","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s11046-023-00727-z","article-title":"Treatment of Invasive Aspergillosis: How It\u2019s Going, Where It\u2019s Heading","volume":"188","year":"2023","journal-title":"Mycopathologia"},{"key":"2026061905552075000_2026.06.17.732805v1.3","doi-asserted-by":"crossref","first-page":"e309","DOI":"10.1097\/HS9.0000000000000309","article-title":"Invasive Aspergillosis in Patients Treated With Ibrutinib","volume":"4","year":"2020","journal-title":"Hemasphere"},{"key":"2026061905552075000_2026.06.17.732805v1.4","doi-asserted-by":"crossref","unstructured":"Friedman DZP , Schwartz IS. 2019. 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