Malassezia and Candida auris: skin microbiome dysbiosis and de-regulation of cutaneous homeostasis

马拉色菌和耳念珠菌：皮肤微生物群失调和皮肤稳态失调

• 批准号: 10661959
• 负责人: JOSEPH HEITMAN
• 金额: $ 22.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661959
• 关键词: Affect; Allergens; Animals; Antibiotics; Antifungal Agents; Atopic Dermatitis; Bacteria; Biology; Calcineurin; Candida; Candida auris; Clinical Pathology; Complex; Consensus; Coupled; Crohn' s disease; Cutaneous; Cystic Fibrosis; Data; Diagnosis; Diagnostic; Disease; Distal; Double Stranded RNA Virus; Double-Stranded RNA; Drug resistance; Eczema; Evolution; Exclusion; Foundations; Functional disorder; Gastrointestinal tract structure; Gene Deletion; Generations; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Health; Homeostasis; Hospitals; Human; Immune System Diseases; Immune response; Immune system; Immunity; In Vitro; Infection; Infectious Skin Diseases; Inflammation; Inflammatory Response; Knowledge; Life Style; Link; Lipids; Lung; Macrophage; Malassezia; Malignant neoplasm of pancreas; Mediating; Microbe; Microbiology; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Nature; Outcome; Pathogenesis; Pathogenicity; Patients; Pattern; Peptide Hydrolases; Phenotype; Play; Prevention approach; Protein Secretion; Proteins; Proteomics; Rhizobium radiobacter; Risk; Risk Factors; Role; STEM research; Satellite RNA; Sepsis; Signal Transduction; Site; Skin; Skin colonization; Systemic infection; Techniques; Testing; Tinea Versicolor; Translations; Viral; Virulence; Virulence Factors; Virus; Yeasts; commensal microbes; drug action; dysbiosis; fungus; genetic manipulation; genetic resource; genetic technology; genome annotation; genome resource; improved; in vivo; in vivo Model; insight; keratinocyte; lipophilicity; microbial host; microbiome; microorganism interaction; mortality; mouse model; mutant; mycobiome; novel; pathogen; pathogenic fungus; pathogenic microbe; prognostic; reference genome; response; skin barrier; skin disorder; skin microbiome; skin microbiota; telomere; tool; transcriptome sequencing; tumor progression; viral RNA

Abstract Malassezia yeasts are lipophilic and are the most abundant fungi of the skin microbiome of warm- blooded animals. In addition to a commensal lifestyle, Malassezia yeasts are associated with skin diseases and also bloodstream infection. Studies have linked Malassezia in the GI tract as a risk factor for Crohn's Disease in patients with CARD9 mutations and potentially in pancreatic cancer progression, whereas Malassezia in the lung has been linked to Cystic Fibrosis exacerbation. In parallel, Candida auris has emerged globally and is frequently drug-resistant and increasingly causing hospital-acquired skin colonization with significant risk of systemic infection with significant morbidity and mortality. Julie Segre and colleagues have developed a mouse model of Candida auris colonization and found that human skin mycobiome dysbiosis, likely caused by antibiotics and antifungal drugs, shifts skin colonization from Malassezia-dominant to Candida-species dominant patterns prior to Candida auris systemic infections. Genetic and genomics studies from our group and others have advanced the state of the art for the study of Malassezia species and their interactions with bacteria and fungi in the skin microbiome and the host. We developed an Agrobacterium tumefaciens approach enabling generation of both random and targeted mutants of two Malassezia species, and applied these tools to study functions of Malassezia genes with roles in drug action and host-pathogen interactions. We have conducted extensive genomic analysis, contributing genome annotation via proteomics and obtaining complete telomere-telomere, well-annotated Malassezia reference genomes. Our past studies on Candida species defined a globally conserved role of calcineurin in fungal pathogenesis, advanced genomics across the Candida pathogenic species complex, and documented that Candida lusitaniae, closely related to Candida auris, has a complete sexual cycle. Our key collaborator Salome LeibundGut-Landmann has developed a murine skin model for Malassezia integral to these studies. Here we propose to study the interactions of Malassezia with Candida auris in dysbiosis of the skin microbiome as a risk factor for systemic infection. In Aim 1 we propose to focus on 1) a novel dsRNA Malassezia mycovirus we discovered and its encoded candidate protein effector by generating and studying strains cured of either or both viral RNAs, and 2) Malassezia secreted proteins (including allergens and proteases) by studying gene deletion mutants as well as random insertion mutants. In Aim 2, Malassezia virus-infected, virus-semi-cured, and virus-cured strains and mutants generated in Aim 1 will be studied with in vitro and in vivo models to define molecular mechanisms of interactions with Candida auris and the host. The studies proposed will advance the field, providing insights as a foundation for studies aiming to elucidate the beneficial roles Malassezia plays as skin commensals that protect the human host from systemic infection by fungal pathogens through competitive and exclusive colonization of the skin microenvironment.

摘要 马拉色酵母是亲脂性的，是温暖地区皮肤微生物组中最丰富的真菌。 有血统的动物。除了共生生活方式之外，马拉色菌还与皮肤病有关 还有血流感染。研究表明胃肠道中的马拉色菌是克罗恩病的危险因素 具有 CARD9 突变且可能导致胰腺癌进展的患者的疾病，而 肺部马拉色菌与囊性纤维化恶化有关。与此同时，耳念珠菌 全球出现，经常产生耐药性，并越来越多地导致医院获得性皮肤病 定植具有显着的全身感染风险，具有显着的发病率和死亡率。朱莉·塞格雷和 同事们开发了耳念珠菌定植的小鼠模型，并发现人类皮肤 真菌生物群失调，可能由抗生素和抗真菌药物引起，使皮肤定植从 在耳念珠菌全身感染之前，马拉色菌占主导地位的念珠菌属占主导地位的模式。 我们小组和其他人的遗传和基因组学研究推进了该研究的最新技术水平 马拉色菌物种及其与皮肤微生物组和宿主中的细菌和真菌的相互作用。我们 开发了一种根癌农杆菌方法，能够生成随机和靶向的 两个马拉色菌物种的突变体，并应用这些工具来研究马拉色菌基因的功能及其作用 药物作用和宿主-病原体相互作用。我们进行了广泛的基因组分析，贡献 通过蛋白质组学进行基因组注释并获得完整的端粒-端粒，注释良好的马拉色菌 参考基因组。我们过去对念珠菌属物种的研究确定了钙调神经磷酸酶在全球范围内保守的作用 真菌发病机制、念珠菌致病物种复合体的高级基因组学，并记录在案 与耳念珠菌密切相关的卢西塔尼亚念珠菌具有完整的性周期。我们的主要合作者 Salome LeibundGut-Landmann 开发了马拉色菌小鼠皮肤模型，作为这些研究的一部分。 在这里，我们建议研究马拉色菌与耳念珠菌在皮肤生态失调中的相互作用 微生物组是全身感染的危险因素。在目标 1 中，我们建议重点关注 1) 一种新型 dsRNA 我们通过生成和研究发现了马拉色菌病毒及其编码的候选蛋白效应子 治愈一种或两种病毒 RNA 的菌株，以及 2) 马拉色菌分泌的蛋白质（包括过敏原和 蛋白酶）通过研究基因缺失突变体以及随机插入突变体。在目标 2 中，马拉色西亚 将研究目标 1 中产生的病毒感染、病毒半治愈和病毒治愈菌株和突变体 体外和体内模型来定义与耳念珠菌和宿主相互作用的分子机制。 提出的研究将推动该领域的发展，为旨在阐明这一问题的研究奠定基础。 马拉色菌作为皮肤共生菌所发挥的有益作用，可保护人类宿主免受全身感染 真菌病原体通过皮肤微环境的竞争性和排他性定植。