{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:43:26Z","timestamp":1790412206004,"version":"4.1.0"},"reference-count":69,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T00:00:00Z","timestamp":1727222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T00:00:00Z","timestamp":1727222400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["R01AI153599, T32GM142621"],"award-info":[{"award-number":["R01AI153599, T32GM142621"]}]},{"name":"HHS | National Institutes of Health","award":["T32GM142621"],"award-info":[{"award-number":["T32GM142621"]}]},{"name":"HHS | National Institutes of Health","award":["R01AI134796"],"award-info":[{"award-number":["R01AI134796"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2024,9,25]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The uridine derivatives UDP-glucose and UDP-\n                      <jats:italic>N<\/jats:italic>\n                      -acetylglucosamine are important for cell wall construction as they are the precursors for the synthesis of \u03b2-1,3-glucan and chitin, respectively. Previous studies have demonstrated attenuated virulence of uridine auxotrophs in mice, which has been attributed to insufficient uridine levels for growth in the host. We have discovered that uridine deprivation in the uridine auxotroph\n                      <jats:italic>ura3<\/jats:italic>\n                      \u0394\u0394 disrupts cell wall architecture by increasing surface mannans, exposing \u03b2-1,3-glucan and chitin, and decreasing UDP-sugar levels. Cell wall architecture and UDP-sugars can be rescued with uridine supplementation. The cell wall architectural disruptions in the\n                      <jats:italic>ura3<\/jats:italic>\n                      \u0394\u0394 mutant also impact immune activation since the mutant elicited greater TNF\u03b1 secretion from RAW264.7 macrophages than wild type. To determine if cell wall defects contributed to decreased virulence in the\n                      <jats:italic>ura3<\/jats:italic>\n                      \u0394\u0394 mutant, we used a murine model of systemic infection. Mice infected with the\n                      <jats:italic>ura3<\/jats:italic>\n                      \u0394\u0394 mutant exhibited increased survival and reduced kidney fungal burden compared with mice infected with wild type. However, suppression of the immune response with cyclophosphamide did not rescue virulence in mice infected with the\n                      <jats:italic>ura3<\/jats:italic>\n                      \u0394\u0394 mutant, indicating the attenuation in virulence of uridine auxotrophs can be attributed to decreased growth in the host but not increased exposure of \u03b2-1,3-glucan. Moreover, the\n                      <jats:italic>ura3<\/jats:italic>\n                      \u0394\u0394 mutant is unable to grow on\n                      <jats:italic>ex vivo<\/jats:italic>\n                      kidney agar, which demonstrates its inability to colonize the kidneys due to poor growth. Thus, although uridine auxotrophy elicits changes to cell wall architecture that increase the exposure of immunogenic polymers, metabolic fitness costs more strongly drive the observed virulence attenuation.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic>Candida albicans<\/jats:italic>\n                        is a common cause of bloodstream infections (candidemia). Treatment of these bloodstream infections is made difficult because of increasing antifungal resistance and drug toxicity. Thus, new tactics are needed for antifungal drug development, with immunotherapy being of particular interest. The cell wall of\n                        <jats:italic>C. albicans<\/jats:italic>\n                        is composed of highly immunogenic polymers, particularly \u03b2-1,3-glucan. However, \u03b2-1,3-glucan is naturally masked by an outer layer of mannoproteins, which hampers the detection of the fungus by the host immune system. Alteration in cell wall components has been shown to increase \u03b2-1,3-glucan exposure; however, it is unknown how the inability to synthesize precursors to cell wall components affects unmasking. Here, we demonstrate how cell wall architecture is altered in response to a deficit in precursors for cell wall synthesis and how uridine is a crucial component of these precursors.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msphere.00287-24","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T09:00:21Z","timestamp":1723107621000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Disruption to\n                    <i>de novo<\/i>\n                    uridine biosynthesis alters \u03b2-1,3-glucan masking in\n                    <i>Candida albicans<\/i>"],"prefix":"10.1128","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4576-072X","authenticated-orcid":false,"given":"Mikayla M.","family":"Mangrum","sequence":"first","affiliation":[{"name":"Department of Microbiology, University of 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