Microbe dependent mechanisms that antagonize intestinal injury repair

拮抗肠道损伤修复的微生物依赖性机制

• 批准号: 10748588
• 负责人: Kevin Newhall
• 金额: $ 5.27万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748588
• 关键词: Adopted; Affect; Automobile Driving; Biopsy; Bone Marrow; Candida albicans; Cell Line; Cells; Chemicals; Chronic; Colon; Complement; Crohn' s disease; Cytology; Data; Disease; Disparity; Effector Cell; Event; Food Additives; Future; Genetic Screening; Germination; Goals; Histoplasmosis; Hyphae; Immune Evasion; Immune response; Impaired wound healing; Impairment; In Vitro; Individual; Infection; Inflammatory; Injury; Interferon Type I; Intestines; Macrophage; Macrophage Activation; Mechanics; Methods; Microbe; Modeling; Molecular; Morphology; Mucous Membrane; Mus; Mycoses; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern recognition receptor; Phagocytosis; Phagolysosome; Phase; Phenotype; Play; Predisposition; Production; RANTES; Reproduction spores; Research; Role; Signal Transduction; Signaling Molecule; Stains; Stress; TNF gene; Testing; Tissues; Transmission Electron Microscopy; Tuberculosis; Ulcer; Variant; Work; Yeasts; antagonist; cell type; chronic infection; chronic inflammatory disease; cytokine; data visualization; fitness; gut microbiome; healing; immunopathology; in vivo; in vivo Model; injury and repair; intestinal injury; member; microbial; microorganism; mouse model; mutant; new therapeutic target; pathogen; repaired; response; therapeutic development; wound healing

PROJECT SUMMARY Debaryomyces hansenii is a fungal member of the gut microbiome and is present within inflamed regions of the intestine in Crohn Disease patients. Patient-derived strains of D. hansenii prolong wound healing in mouse chemical and mechanical intestinal injury models. Mechanisms of pathogenicity of D. hansenii are not well understood, though macrophages are a key effector cell type in the delayed wound healing phenotype. The objective of the proposed work is to define mechanisms of innate host response to D. hansenii using in vitro macrophage models and define microbial mechanisms of impaired wound repair using in vivo models of intestinal injury. Our preliminary data visualizing phagocytosed D. hansenii with transmission electron microscopy and cytological staining demonstrate certain macrophages phagocytose and are unable to clear D. hansenii. Macrophages that do not clear D. hansenii also do not produce TNF-α in response to D. hansenii. In aim 1, I test the hypothesis that TNF-α supports macrophages clearance of phagocytosed D. hansenii and identify the pattern recognition receptors responsible for TNF-α production. In aim 2, I examine microbial morphologic-transitions as an immune evasion mechanism in vitro and in vivo. My preliminary data suggest that vegetative D. hansenii yeast induce more potent pro-inflammatory cytokine production than spores of D. hansenii, and spores persist within macrophage cell lines in vitro. This project will define microbial mechanisms that permit D. hansenii persistence within the intestine and antagonism of injury repair. Successful completion of these aims will define mechanisms of host-response to D. hansenii and microbial-evasion of macrophage clearance that will lead the identification of novel therapeutic targets for treating the subset of Crohn Disease patients with tissue associated D. hansenii.

项目总结 汉森变形杆菌是肠道微生物群中的一种真菌成员，存在于肠道炎症区域。 克罗恩病患者的肠道。患者来源的汉森葡萄球菌延长小鼠伤口愈合 化学性和机械性肠损伤模型。汉森假丝酵母菌致病机制尚不清楚 虽然巨噬细胞是伤口延迟愈合表型中的关键效应细胞类型。这个 这项拟议工作的目的是确定先天宿主对汉森登革热的反应机制。 体外巨噬细胞模型及利用体内研究创面受损修复的微生物机制 肠损伤模型。我们的初步数据显示通过传播吞噬了汉森杜氏菌 电子显微镜和细胞学染色显示某些巨噬细胞吞噬并不能 清除D·汉森。不清除汉森杜氏菌的巨噬细胞也不会产生肿瘤坏死因子-α。 汉森。在目标1中，我测试了肿瘤坏死因子-α支持巨噬细胞清除吞噬的D。 Hansenii，并确定负责产生肿瘤坏死因子-α的模式识别受体。在《目标2》中，我考察 微生物形态转变在体外和体内作为免疫逃避机制。我的初步数据 提示营养状态下的汉森假丝酵母比孢子能诱导更强的促炎细胞因子的产生 体外培养的巨噬细胞系内存留有孢子。该项目将定义微生物 允许汉森假丝酵母菌在肠道内持续存在和拮抗损伤修复的机制。成功 这些目标的完成将确定宿主对汉森登革热的反应机制和微生物逃避 巨噬细胞清除将导致确定治疗克罗恩亚型的新治疗靶点 疾病患者与组织相关的汉森葡萄球菌。