Cell aggregation mediated by ACE2 deletion in Candida auris modulates fungal colonization and host immune responses in the skin.

IF 3.7 2区 生物学 Q2 MICROBIOLOGY mSphere Pub Date : 2024-10-30 DOI:10.1128/msphere.00734-24
Abishek Balakumar, Abigail Cox, Shankar Thangamani
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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.

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白色念珠菌中 ACE2 缺失介导的细胞聚集调节真菌在皮肤中的定植和宿主免疫反应。
白色念珠菌(Candida auris)是一种新出现的多重耐药真菌病原体,可在皮肤上定植并导致住院病人的侵袭性感染。多细胞聚集表型在 C. auris 分离物中被广泛报道,但其在皮肤定植和宿主免疫反应中的作用尚不清楚。在本研究中,我们通过删除 C. auris 中的 ACE2 基因产生了聚集表型,并使用 C. auris 皮肤感染小鼠皮内模型测定了真菌定植和宿主免疫反应。我们的结果表明,与非聚集野生型和 ACE2 重整合株相比,感染 ace2Δ 株的小鼠在感染后 3 天和 14 天的真菌负荷量明显较低。ace2Δ的定植与CD11b+ Ly6G+中性粒细胞的招募增加以及CD11b+ Ly6 Chi炎性单核细胞和CD11b+ MHCII+ CD64+巨噬细胞的聚集减少有关。此外,ace2Δ感染小鼠皮肤组织中的Th17细胞和3型先天性淋巴细胞(ILCs)显著增加。我们的研究结果表明,ACE2缺失介导的C. auris聚集表型可诱导有效的中性粒细胞和IL-17介导的免疫反应,并减少真菌在皮肤中的定植。C. auris 分离物表现出形态异质性,临床上经常报告 C. auris 的多细胞聚集表型。了解真菌形态在皮肤微环境中的定植、持续存在和免疫反应中的作用将可能应用于临床诊断和新型预防与治疗措施。在这里,我们利用小鼠皮内感染模型,确定了由于 ACE2 基因缺失导致的 C. auris 的聚集表型会引起小鼠潜在的先天性和适应性免疫反应。这些观察结果将有助于解释C. auris聚集表型在皮肤定植和免疫反应方面的差异,并为开发新型抗真菌疗法打开大门。
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来源期刊
mSphere
mSphere Immunology and Microbiology-Microbiology
CiteScore
8.50
自引率
2.10%
发文量
192
审稿时长
11 weeks
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.
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