{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T15:06:59Z","timestamp":1785942419366,"version":"3.56.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dematiaceous fungi cause chronic, invasive cutaneous infections that are difficult to eradicate and frequently relapse despite antifungal therapy. Although host immunity is critical for controlling these infections, the temporal organization of immune responses and the underlying immunometabolic programs remain poorly defined. In particular, how macrophage dynamics and chemokine signaling shape antifungal immunity over time is largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using\n                      <jats:italic>Phialophora verrucosa<\/jats:italic>\n                      as a representative dematiaceous fungus, we established a murine subcutaneous infection model and performed time-resolved transcriptomic and proteomic analyses across the course of infection. Immune cell composition, pathway dynamics, and metabolic signatures were systematically characterized. To functionally validate key regulatory axes identified by multi-omics analyses, bone marrow\u2013derived macrophages and dendritic cells from wild-type and\n                      <jats:italic>Ccr2<\/jats:italic>\n                      knockout mice were subjected to\n                      <jats:italic>in vitro<\/jats:italic>\n                      fungus\u2013cell coculture assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Time-resolved multi-omics analysis revealed that days 7\u201314 post-infection constituted a critical transition phase of the host immune response, coinciding with lesion regression and pathogen clearance. This stage featured marked activation of pathways governing antigen presentation, phagosome formation and inflammatory signaling. Macrophages underwent dynamic changes in both abundance and phenotype during this period, accompanied by the upregulation of glycolysis- and lactate metabolism-related pathways. Co-expression and interaction network analysis further identified\n                      <jats:italic>Ccr2<\/jats:italic>\n                      as a core hub within the chemokine signaling network.\n                      <jats:italic>in vitro<\/jats:italic>\n                      functional assays demonstrated that while\n                      <jats:italic>Ccr2<\/jats:italic>\n                      deficiency did not compromise the phagocytic or fungicidal activity of macrophages, it significantly diminished their chemotactic capacity toward\n                      <jats:italic>P. verrucosa<\/jats:italic>\n                      conidia. Under infection stimulation, loss of\n                      <jats:italic>Ccr2<\/jats:italic>\n                      also promoted M1-type polarization of macrophages, along with enhanced maturation of dendritic cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study elucidates the dynamic remodeling of immunometabolism centered on macrophages during\n                      <jats:italic>P. verrucosa<\/jats:italic>\n                      infection, and demonstrates that the CCL2\/CCR2 biological axis contributes to host antifungal immunity mainly by modulating immune cell recruitment and the balance of inflammatory phenotypes. These findings provide a novel theoretical basis for understanding the immunoregulatory mechanisms of dematiaceous fungal infections and developing potential immunological intervention strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1893423","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T14:28:40Z","timestamp":1785940120000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Time-resolved multi-omics reveals macrophage-centered immunometabolic remodeling in cutaneous dematiaceous fungal infection"],"prefix":"10.3389","volume":"17","author":[{"given":"Yongqiang","family":"Fu","sequence":"first","affiliation":[{"name":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"Liu","sequence":"additional","affiliation":[{"name":"Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Dong","sequence":"additional","affiliation":[{"name":"Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Guo","sequence":"additional","affiliation":[{"name":"Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiejie","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Affiliated Dermatology Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]},{"name":"Department of Dermatology, The Fifth People\u2019s Hospital of Hainan Province","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Affiliated Dermatology Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]},{"name":"Department of Dermatology, The Fifth People\u2019s Hospital of Hainan Province","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Medical Mycology Research Center, Chiba University","place":["Chiba, Japan"]},{"name":"Molecular Chirality Research Center, Chiba University","place":["Chiba, Japan"]},{"name":"Plant Molecular Science Center, Chiba University","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.idc.2024.11.006","article-title":"Dematiaceous molds","volume":"39","author":"Li","year":"2025","journal-title":"Infect Dis Clinics North America"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00032-16","article-title":"Chromoblastomycosis","volume":"30","author":"Queiroz-Telles","year":"2016","journal-title":"Clin Microbiol Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/jof8090963","article-title":"Biofilm formation by chromoblastomycosis fungi Fonsecaea pedrosoi and Phialophora verrucosa: Involvement with antifungal resistance","volume":"8","author":"Sousa","year":"2022","journal-title":"J Fungi (Basel)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2020.1724994","article-title":"Aspartic peptidase of Phialophora verrucosa as target of HIV peptidase inhibitors: Blockage of its enzymatic activity and interference with fungal growth and macrophage interaction","volume":"35","author":"Granato","year":"","journal-title":"J Enzyme Inhib Med Chem"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.895329","article-title":"Phaeohyphomycosis in China","volume":"12","author":"He","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2024.03.056","article-title":"Dermatologic fungal neglected tropical diseases-part i. 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