{"title":"白色念珠菌 Hog1 MAP 激酶对小鼠皮肤的定殖和皮内持久性至关重要。","authors":"Raju Shivarathri, Manju Chauhan, Abhishek Datta, Diprasom Das, Adela Karuli, Ariel Aptekmann, Sabrina Jenull, Karl Kuchler, Shankar Thangamani, Anuradha Chowdhary, Jigar V Desai, Neeraj Chauhan","doi":"10.1128/mbio.02748-24","DOIUrl":null,"url":null,"abstract":"<p><p><i>Candida auris</i>, a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic <i>C. auris</i> infections have now been reported in more than 50 countries, with mortality rates of 30%-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that <i>C. auris,</i> unlike most <i>Candida</i> species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for <i>C. auris</i> skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that <i>C. auris</i> Hog1 mitogen-activated protein kinase is essential for efficient skin colonization, intradermal persistence as well as systemic virulence. RNA-seq analysis of wild-type parental and <i>hog1</i>Δ mutant strains revealed marked downregulation of genes involved in processes such as cell adhesion, cell wall rearrangement, and pathogenesis in <i>hog1</i>Δ mutant compared to the wild-type parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell wall architecture, as the <i>hog1</i>Δ mutant demonstrated a significant increase in cell-surface β-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation <i>in vitro</i> and fungal survival when challenged with primary murine macrophages and neutrophils <i>ex vivo</i>. Collectively, these findings have important implications for understanding the <i>C. auris</i> skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections.</p><p><strong>Importance: </strong><i>Candida auris</i> is a World Health Organization fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention. <i>C. auris</i> has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of <i>C. auris</i>. Therefore, understanding <i>C. auris</i> skin colonization mechanisms is critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of <i>C. auris</i> skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of <i>C. auris</i> skin colonization. These findings lay the foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0274824"},"PeriodicalIF":5.1000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558994/pdf/","citationCount":"0","resultStr":"{\"title\":\"The <i>Candida auris</i> Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence.\",\"authors\":\"Raju Shivarathri, Manju Chauhan, Abhishek Datta, Diprasom Das, Adela Karuli, Ariel Aptekmann, Sabrina Jenull, Karl Kuchler, Shankar Thangamani, Anuradha Chowdhary, Jigar V Desai, Neeraj Chauhan\",\"doi\":\"10.1128/mbio.02748-24\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><i>Candida auris</i>, a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. 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Consistent with these data, we found a prominent role for Hog1 in maintaining cell wall architecture, as the <i>hog1</i>Δ mutant demonstrated a significant increase in cell-surface β-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation <i>in vitro</i> and fungal survival when challenged with primary murine macrophages and neutrophils <i>ex vivo</i>. Collectively, these findings have important implications for understanding the <i>C. auris</i> skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections.</p><p><strong>Importance: </strong><i>Candida auris</i> is a World Health Organization fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention. <i>C. auris</i> has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. 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引用次数: 0
摘要
念珠菌是一种具有多重耐药性的人类真菌病原体,2009 年首次在日本被发现。从那时起,50 多个国家报告了系统性念珠菌感染,死亡率高达 30%-60%。造成其在医院间和医院内高度克隆传播的一个主要因素是,与大多数念珠菌不同,阿脲酵母菌具有独特的皮肤滋养性,可在人体皮肤上长期存在。然而,人们对 C. auris 皮肤定殖、皮内持久性和全身毒性的分子机制知之甚少。在此,我们报告了 C. auris Hog1 丝裂原活化蛋白激酶对皮肤的高效定殖、皮内持久性和全身毒力至关重要。对野生型亲本和 hog1Δ 突变株的 RNA-seq 分析显示,与野生型亲本相比,hog1Δ 突变株中参与细胞粘附、细胞壁重排和致病过程的基因明显下调。与这些数据一致的是,我们发现 Hog1 在维持细胞壁结构方面起着重要作用,因为 hog1Δ 突变体的细胞表面 β-葡聚糖暴露显著增加,同时几丁质含量减少。此外,我们还观察到,Hog1 是体外生物膜形成和真菌在小鼠原代巨噬细胞和中性粒细胞体内存活的必要条件。总之,这些发现对了解阿氏念珠菌的皮肤粘附机制和血液感染前皮肤上皮细胞层的渗透具有重要意义:重要意义:白色念珠菌是世界卫生组织重点关注的真菌病原体,也是美国疾病控制和预防中心认定的一种紧迫的公共卫生威胁。念珠菌具有在人体皮肤上定植的独特能力。它还能在医疗环境的非生物表面长期存在。这些特性促进了 C. auris 在医院间和医院内的克隆传播。因此,了解 C. auris 的皮肤定植机制对于感染控制至关重要,尤其是在医院和疗养院。然而,尽管它与临床密切相关,但人们对 C. auris 皮肤定植机制的分子和遗传基础却知之甚少。在本文中,我们展示了关于 Hog1 MAP 激酶作为 C. auris 皮肤定植关键调控因子的鉴定数据。这些发现为进一步确定促进真菌在人体皮肤上持续存在的独特机制奠定了基础。
The Candida auris Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence.
Candida auris, a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic C. auris infections have now been reported in more than 50 countries, with mortality rates of 30%-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that C. auris Hog1 mitogen-activated protein kinase is essential for efficient skin colonization, intradermal persistence as well as systemic virulence. RNA-seq analysis of wild-type parental and hog1Δ mutant strains revealed marked downregulation of genes involved in processes such as cell adhesion, cell wall rearrangement, and pathogenesis in hog1Δ mutant compared to the wild-type parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell wall architecture, as the hog1Δ mutant demonstrated a significant increase in cell-surface β-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation in vitro and fungal survival when challenged with primary murine macrophages and neutrophils ex vivo. Collectively, these findings have important implications for understanding the C. auris skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections.
Importance: Candida auris is a World Health Organization fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention. C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris. Therefore, understanding C. auris skin colonization mechanisms is critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay the foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.
期刊介绍:
mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.