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Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis

17 型口腔念珠菌病免疫的宿主和真菌调控

基本信息

批准号：
10673918
负责人：
Sarah L Gaffen
金额：
$ 57.74万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673918
关键词：
Acceleration Acquired Immunodeficiency Syndrome Adaptive Immune System Adrenal Cortex Hormones Antifungal Agents Area Automobile Driving CCAAT-Enhancer-Binding Proteins Candida albicans Candidiasis Cell Communication Cell Compartmentation Cell Differentiation process Cell Proliferation Cell membrane Cells Client Cytokine Receptors Cytokine Signaling Data Data Set Disease Elderly Epidermal Growth Factor Receptor Epithelial Cells Epithelium Event Family Family member Funding Goals Grant Homeostasis Host Defense Human Hyphae IL17 gene Immune Immune response Immune system Immunity Immunology Immunosuppressive Agents Individual Infant Infection Inhalation Innate Immune System Interleukin-1 Laboratories Lead Location Lymphocyte MAP Kinase Gene Mediating Microbe Molecular Morphology Mouth Diseases Mucosal Immunity Mucous Membrane Mus Mycoses NF-kappa B Neutrophil Infiltration Oral Oral candidiasis Oral cavity Oral mucous membrane structure Pathway interactions Peptides Permeability Pharmaceutical Preparations Production Property RNA Stability RNA-Binding Proteins Regulation Reporting Research STAT3 gene Signal Induction Signal Pathway Signal Transduction Signal Transduction Induction Site Source Stromal Cells System T cell response T-Lymphocyte TIS11 protein Tissues Toxin Transcript Translations Transplant Recipients Up-Regulation Virulence Virulence Factors Work antimicrobial peptide asthmatic patient cell type chemokine chemotherapy cytokine draining lymph node epithelial repair fungus immune function interest interleukin-22 interleukin-23 model organism mucosal vaccine oral cavity epithelium oral immunity oral infection oral pathogen oral tissue oropharyngeal thrush p38 Mitogen Activated Protein Kinase pathogen pathogenic fungus posttranscriptional response single-cell RNA sequencing stem tissue regeneration tissue repair trait transcription factor

项目摘要

Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection associated with immune deficiency, particularly in the T cell compartment. C. albicans is a commensal fungus that is the dominant causative species of OPC, and its key virulence trait is the ability to form invasive hyphae. This morphologic transition in the fungus triggers ‘danger’ responses in oral epithelial cells (OECs), which are the first cell types to encounter this microbe. In 2009, we showed that an effective immune response to mucosal candidiasis in mice requires signaling by the cytokine IL-17 (IL-17A). The importance of IL-17 was confirmed in humans with IL-17R-deficiencies. Using mice as a model organism, we showed that in naïve settings (i.e., innate responses), IL-17 is made by two innate lymphocyte cell subsets: gd-T and ‘natural’ Th17 cells (nTh17). In recall (i.e., adaptive) responses, IL-17 is additionally made by conventional CD4+Th17 cells, which augment the innate response to accelerate fungal clearance. Collectively, IL-17+ cells comprise “Type 17” immunity. Regardless of source, IL-17 signals through a heterodimer of IL-17RA and IL-17RC, which is highly expressed on cells of the stromal and epithelial compartments. The initiating event in OPC is exposure of OECs to C. albicans. However, it remains unclear how early epithelial recognition events lead to activation of Type 17 responses, and why these responses occur only in response to hyphae. In a landmark discovery the co-I (Dr. Naglik) showed that the danger response in OECs is activated by a virulence factor, Candidalysin, the first pore-forming peptide toxin identified in any human fungal pathogen. Candidalysin is secreted only by hyphae and permeabilizes OEC membranes. Candidalysin triggers a MAPK-dependent pathway, leading to upregulation of cytokines, chemokines and antimicrobial peptides that are essential for immunity to OPC. Our overarching goal in this continuation is to define in depth the mechanisms by which host-and pathogen-derived factors coordinate effective Type 17 immunity against C. albicans.

口咽念珠菌病 (OPC) 是一种机会性真菌感染，与免疫缺陷，尤其是 T 细胞区室的免疫缺陷。白色念珠菌是共生体真菌是 OPC 的主要致病菌，其主要毒力特征是形成侵入性菌丝的能力。真菌的这种形态转变触发了口腔上皮细胞（OEC）中的“危险”反应，这是第一个产生危险的细胞类型遇到这种微生物。 2009年，我们证明了有效的免疫反应小鼠粘膜念珠菌病需要细胞因子 IL-17 (IL-17A) 发出信号。这 IL-17 的重要性在 IL-17R 缺陷的人类中得到证实。使用小鼠作为在模型生物体中，我们发现在幼稚环境（即先天反应）中，IL-17 是产生的由两种先天淋巴细胞亚群组成：gd-T 和“天然”Th17 细胞 (nTh17)。回忆中（即适应性）反应，IL-17 另外由常规 CD4+Th17 细胞产生，这增强了加速真菌清除的先天反应。总的来说，IL-17+ 细胞具有“17 型”免疫力。无论来源如何，IL-17 信号通过 IL-17RA 和 IL-17RC 的异二聚体，在基质细胞上高表达和上皮区室。 OPC 的起始事件是 OEC 暴露于 C. 白色念珠菌。然而，目前尚不清楚早期上皮识别事件如何导致 17 型反应的激活，以及为什么这些反应仅在响应时发生菌丝。在一项具有里程碑意义的发现中，co-I（Naglik 博士）表明，危险反应 OEC 中的念珠菌溶酶 (Candidalysin) 被毒力因子激活，这是第一个成孔肽在任何人类真菌病原体中发现的毒素。念珠菌溶素仅由菌丝分泌并透化 OEC 膜。念珠菌溶酶触发 MAPK 依赖性途径，导致细胞因子、趋化因子和抗菌肽的上调这对于 OPC 免疫至关重要。我们在此延续的总体目标是深入定义宿主和病原体衍生因子的机制协调针对白色念珠菌的 17 型有效免疫力。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Candidalysin delivery to the invasion pocket is critical for host epithelial damage induced by Candida albicans.

DOI：
10.1111/cmi.13378
发表时间：
2021-10
期刊：
Cellular microbiology
影响因子：
3.4
作者：
Mogavero S;Sauer FM;Brunke S;Allert S;Schulz D;Wisgott S;Jablonowski N;Elshafee O;Krüger T;Kniemeyer O;Brakhage AA;Naglik JR;Dolk E;Hube B
通讯作者：
Hube B

The Human Mucosal Mycobiome and Fungal Community Interactions.

DOI：
10.3390/jof3040056
发表时间：
2017-10-07
期刊：
Journal of fungi (Basel, Switzerland)
影响因子：
0
作者：
Witherden EA;Shoaie S;Hall RA;Moyes DL
通讯作者：
Moyes DL

Albumin Neutralizes Hydrophobic Toxins and Modulates Candida albicans Pathogenicity.

DOI：
10.1128/mbio.00531-21
发表时间：
2021-06-29
期刊：
mBio
影响因子：
6.4
作者：
Austermeier S;Pekmezović M;Porschitz P;Lee S;Kichik N;Moyes DL;Ho J;Kotowicz NK;Naglik JR;Hube B;Gresnigt MS
通讯作者：
Gresnigt MS

Candida albicans biofilms and polymicrobial interactions.