{"title":"Cell aggregation mediated by <i>ACE2</i> deletion in <i>Candida auris</i> modulates fungal colonization and host immune responses in the skin.","authors":"Abishek Balakumar, Abigail Cox, Shankar Thangamani","doi":"10.1128/msphere.00734-24","DOIUrl":null,"url":null,"abstract":"<p><p><i>Candida auris</i> is an emerging multi-drug-resistant fungal pathogen that colonizes the skin and causes invasive infections in hospitalized patients. Multi-cellular aggregative phenotype is widely reported in the <i>C. auris</i> isolates, but its role in skin colonization and host immune response is not yet known. In this study, we generated aggregative phenotype by deleting the <i>ACE2</i> gene in <i>C. auris</i> and determined the fungal colonization and host immune response using an intradermal mouse model of <i>C. auris</i> skin infection. Our results indicate that mice infected with <i>ace2</i>Δ strain had significantly lower fungal load after 3 and 14 days post-infections compared to the non-aggregative wild-type and the <i>ACE2</i> reintegrated strain. The colonization of <i>ace2</i>Δ is associated with increased recruitment of CD11b<sup>+</sup> Ly6G<sup>+</sup> neutrophils and decreased accumulation of CD11b<sup>+</sup> Ly6 C<sup>hi</sup> inflammatory monocytes and CD11b<sup>+</sup> MHCII<sup>+</sup> CD64<sup>+</sup> macrophages. Furthermore, Th17 cells and type 3 innate lymphoid cells (ILCs) were significantly increased in the skin tissue of <i>ace2</i>Δ infected mice. Our findings suggest that aggregative phenotype mediated by <i>ACE2</i> deletion in <i>C. auris</i> induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin.IMPORTANCE<i>C. auris</i> is a rapidly emerging fungal pathogen that can colonize hospitalized patients, especially in skin tissue, and cause invasive infections. <i>C. auris</i> isolates exhibit morphological heterogeneity, and the multicellular aggregative phenotype of <i>C. auris</i> is reported frequently in clinical settings. Understanding the role of fungal morphotypes in colonization, persistence, and immune response in the skin microenvironment will have potential applications in clinical diagnosis and novel preventive and therapeutic measures. Here, we utilized the murine model of intradermal infection and determined that the aggregative phenotype of <i>C. auris</i> as the result of <i>ACE2</i> gene deletion elicits potential innate and adaptive immune responses in mice. These observations will help explain the differences in the skin colonization and immune responses of the aggregative morphotype of <i>C. auris</i> and open the door to developing novel antifungal therapeutics.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"mSphere","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1128/msphere.00734-24","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Candida auris is an emerging multi-drug-resistant fungal pathogen that colonizes the skin and causes invasive infections in hospitalized patients. Multi-cellular aggregative phenotype is widely reported in the C. auris isolates, but its role in skin colonization and host immune response is not yet known. In this study, we generated aggregative phenotype by deleting the ACE2 gene in C. auris and determined the fungal colonization and host immune response using an intradermal mouse model of C. auris skin infection. Our results indicate that mice infected with ace2Δ strain had significantly lower fungal load after 3 and 14 days post-infections compared to the non-aggregative wild-type and the ACE2 reintegrated strain. The colonization of ace2Δ is associated with increased recruitment of CD11b+ Ly6G+ neutrophils and decreased accumulation of CD11b+ Ly6 Chi inflammatory monocytes and CD11b+ MHCII+ CD64+ macrophages. Furthermore, Th17 cells and type 3 innate lymphoid cells (ILCs) were significantly increased in the skin tissue of ace2Δ infected mice. Our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin.IMPORTANCEC. auris is a rapidly emerging fungal pathogen that can colonize hospitalized patients, especially in skin tissue, and cause invasive infections. C. auris isolates exhibit morphological heterogeneity, and the multicellular aggregative phenotype of C. auris is reported frequently in clinical settings. Understanding the role of fungal morphotypes in colonization, persistence, and immune response in the skin microenvironment will have potential applications in clinical diagnosis and novel preventive and therapeutic measures. Here, we utilized the murine model of intradermal infection and determined that the aggregative phenotype of C. auris as the result of ACE2 gene deletion elicits potential innate and adaptive immune responses in mice. These observations will help explain the differences in the skin colonization and immune responses of the aggregative morphotype of C. auris and open the door to developing novel antifungal therapeutics.
期刊介绍:
mSphere™ is a multi-disciplinary open-access journal that will focus on rapid publication of fundamental contributions to our understanding of microbiology. Its scope will reflect the immense range of fields within the microbial sciences, creating new opportunities for researchers to share findings that are transforming our understanding of human health and disease, ecosystems, neuroscience, agriculture, energy production, climate change, evolution, biogeochemical cycling, and food and drug production. Submissions will be encouraged of all high-quality work that makes fundamental contributions to our understanding of microbiology. mSphere™ will provide streamlined decisions, while carrying on ASM''s tradition for rigorous peer review.