{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:11:32Z","timestamp":1788757892575,"version":"build-2803163510"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pulmonary mucormycosis is a life-threatening fungal infection with a mortality rate exceeding 50%, and diabetes mellitus is one of its strongest risk factors. However, the molecular mechanisms linking diabetes to impaired pulmonary innate immunity remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A streptozotocin-induced type 1 diabetes (T1D) mouse model was used to investigate host responses to intratracheal\n                      <jats:italic>Cunninghamella bertholletiae<\/jats:italic>\n                      infection. Genetic Axl deficiency, pharmacological Axl inhibition with BGB324, histopathological analyses, and ex vivo and\n                      <jats:italic>in vitro<\/jats:italic>\n                      macrophage assays were performed to define the role of the Gas6\/Axl axis in antifungal immunity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      T1D mice exhibited rapid mortality after pulmonary\n                      <jats:italic>C. bertholletiae<\/jats:italic>\n                      infection, accompanied by markedly impaired early neutrophil recruitment. Elevated lung and serum levels of growth arrest-specific protein 6 (Gas6) were intrinsic features of the diabetic state and correlated with blood glucose levels. Genetic ablation or pharmacological blockade of Axl restored macrophage chemokine responses, increased neutrophil recruitment into the airspace, reduced fungal burden, and significantly improved survival in T1D mice. Mechanistically, the Gas6\/Axl axis directly suppressed fungus-induced chemokine production by alveolar macrophages, establishing a pre-existing state of innate immune hyporesponsiveness before infection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings identify the Gas6\/Axl axis as a mechanistic link between diabetes and impaired pulmonary innate immunity. Targeting this pathway may represent a promising host-directed therapeutic strategy for pulmonary mucormycosis in patients with diabetes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1939483","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:23:34Z","timestamp":1788755014000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gas6\/Axl-mediated macrophage hyporesponsiveness drives severe pulmonary mucormycosis in diabetic mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Shotaro","family":"Kondo","sequence":"first","affiliation":[{"name":"Department of Microbiology, Tokyo Medical University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keito","family":"Owaki","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tokyo Medical University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gento","family":"Hamasaki","sequence":"additional","affiliation":[{"name":"Department of Immunology, Nara Medical University","place":["Nara, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Inukai","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tokyo Medical University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jotaro","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tokyo Medical University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Immunology, Nara Medical University","place":["Nara, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tokyo Medical University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehiko","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tokyo Medical University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3092","DOI":"10.3390\/diagnostics12123092","article-title":"Clinical phenotypes of COVID-19 associated mucormycosis (CAM): A comprehensive review","volume":"12","author":"Almyroudi","year":"2022","journal-title":"Diagnostics (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"17968","DOI":"10.1038\/s41598-021-96720-x","article-title":"Impact of overlapping risks of type 2 diabetes and obesity on coronavirus disease severity in the United States","volume":"11","author":"Ando","year":"2021","journal-title":"Sci. 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