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This study aims to investigate the pattern of systemic immune responses triggered by <jats:italic>C. albicans<\/jats:italic> with disease associated variation of Sap2, identifying the novel evasion strategies utilized by clinical isolates. Specifically, a variation in clinical isolates is identified at nucleotide position 817 (G to T). This homozygous variation causes the 273rd amino acid exchange from valine to leucine, close to the proteolytic activation center of Sap2. The mutant (Sap2\u2010273L) generated from SC5314 (Sap2\u2010273V) background carrying the V273L variation within Sap2\u00a0displays higher pathogenicity. In comparison to mice infected with Sap2\u2010273V strain, mice infected with Sap2\u2010273L exhibit less complement activation indicated by less serum C3a generation and weaker C3b deposition in the kidney. This inhibitory effect is mainly achieved by Sap2<jats:sub>273L<\/jats:sub>\u2010mediated stronger degradation of C3\u00a0and C3b. Furthermore, mice infected with Sap2\u2010273L strain exhibit more macrophage phenotype switching from M0\u00a0to M2\u2010like and more TGF\u2010<jats:italic>\u03b2<\/jats:italic> release which further influences T cell responses, generating an immunosuppressed cellular microenvironment characterized by more Tregs and exhausted T cell formation. In summary, the disease\u2010associated sequence variation of Sap2\u00a0enhances pathogenicity by complement evasion and M2\u2010like phenotype switching, promoting a more efficient immunosuppressed microenvironment.<\/jats:p>","DOI":"10.1002\/advs.202206713","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T00:50:07Z","timestamp":1684716607000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Sequence Variation of <i>Candida albicans<\/i> Sap2 Enhances Fungal Pathogenicity via Complement Evasion and Macrophage M2\u2010Like Phenotype Induction"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5836-9511","authenticated-orcid":false,"given":"Lan","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine Union Hospital Tongji Medical College Huazhong University of Science and 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