Role of S.aureus in Cutaneous T Cell Lymphoma Pathogenesis

金黄色葡萄球菌在皮肤 T 细胞淋巴瘤发病机制中的作用

基本信息

批准号：
10620254
负责人：
Sergei Borisovich Koralov
金额：
$ 54.18万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2022-05-10 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620254
关键词：
Abscess Address Animal Model Antibiotic Therapy Bacteria Bacterial Infections Benign Biopsy Specimen Blood Blood typing procedure Cell Survival Cells Characteristics Chronic Clinical Clonal Evolution Coculture Techniques Cutaneous T-cell lymphoma Data Dermal Development Disease Disease Progression Disease model Endothelial Cells Environment Epithelial Cells Epithelium Epitopes Etiology Exposure to Future Gene Rearrangement Genes Genetic Predisposition to Disease Genetic Transcription Genetically Engineered Mouse Genus staphylococcus Germ-Free Gnotobiotic High Prevalence House mice Human Immune In Vitro Individual Inflammation Inflammatory Link Lymphocyte Malignant - descriptor Malignant Neoplasms Methods Microbe Modeling Mutation Non-Hodgkin&apos s Lymphoma Organism Pathogenesis Pathologic Pathway interactions Patients Play Population Production Proliferating Proteins Protocols documentation Research Resolution Role Severity of illness Site Skin Skin Plaques Specimen Standardization Staphylococcus aureus Superantigens Surface Surveys T-Cell Activation T-Cell Lymphoma T-Cell Proliferation T-Cell Receptor Genes T-Cell Transformation T-Lymphocyte Therapeutic Therapeutic Intervention Time Toxin Tropism Virulence Factors Work advanced disease biobank cancer cell cell transformation chemokine clinical center commensal bacteria cytokine epidemiology study experimental study genetic risk factor genome sequencing high throughput technology improved in vivo insight lymphadenopathy microbial microbial products mouse model multimodality neoplastic cell novel pathobiont pathogenic bacteria permissiveness single cell technology single-cell RNA sequencing skin microbiota transcriptomics tumor tumor microenvironment

项目摘要

Abstract Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of blood-related cancers characterized by chronic inflammation and accumulation of malignant T cells in the skin. Among lymphomas, CTCL is uniquely characterized by the striking dermal tropism of transformed cells—where exposure to microbes might contribute to disease etiology. CTCL patients often succumb to bacterial infections, and a correlation between the presence of certain strains of Staphylococcus aureus and disease severity has been observed. Commensal and pathogenic bacteria can influence differentiation of naïve T lymphocytes, trigger proliferation and activation of T cells through production of superantigens (SAgs), and create a permissive microenvironment for tumor cells by influencing chemokine and cytokine expression. We hypothesize that, along with genetic predisposition of an individual and mutations acquired by T cells or T lymphocyte precursors, exposure to S. aureus and SAgs produced by some strains of this pathobiont promotes malignant transformation and clonal evolution in CTCL. Prior research by other groups and our preliminary studies implicate S. aureus specifically in CTCL pathogenesis. We will isolate, sequence and study S. aureus isolates from the skin of CTCL patients (from tumor sites and unaffected skin) and determine the repertoire of toxins and SAgs produced by these strains. We anticipate that CTCL-associated isolates will differ in both the ability to produce large numbers of SAg types per organism and the distribution of their SAg gene content. We will use in vitro methods to evaluate how SAgs and other toxins and exoproteins produced by skin microbiota of CTCL patients contribute to T cell activation, proliferation, and malignant transformation. To further understand the contribution of S. aureus to CTCL pathogenesis and to demonstrate a causal connection between S. aureus colonization and malignant disease, we will use our new animal model of CTCL and our germ-free facility to examine the impact of microbial exposure on CTCL initiation and progression. We will also take advantage of cutting-edge, single-cell, high-throughput technology that enables simultaneous analysis of surface epitopes, T cell receptor gene rearrangements, and transcriptomics to achieve unprecedented resolution of the tumor microenvironment in CTCL and to examine changes in the microenvironment upon S. aureus colonization. The studies outlined in our proposal will provide significant insight into CTCL pathogenesis and will inform development of future therapies that are more targeted and less toxic than current chemotherapeutic approaches.

抽象的皮肤T细胞淋巴瘤（CTCLS）是一组与血液有关的癌症的群体通过慢性炎症和皮肤上恶性T细胞的积累。在淋巴瘤中，CTCL为独特的特征是转化的细胞的醒目的真皮向热，在其中接触微生物可能有助于疾病病因。 CTCL患者经常屈服于细菌感染，并在已经观察到了金黄色葡萄球菌和疾病严重程度的某些菌株的存在。共生和致病细菌会影响幼稚T淋巴细胞的分化，触发增殖通过产生超抗原（SAG）的T细胞激活T细胞，并创建允许的通过影响趋化因子和细胞因子表达的肿瘤细胞微环境。我们假设这一点，以及个体的遗传易感和T细胞或T淋巴细胞获得的突变前体，暴露于金黄色葡萄球菌和该病原体的某些菌株产生的垂体会促进恶性肿瘤 CTCL中的转化和克隆进化。其他小组的事先研究和我们的初步研究牵涉到金黄色葡萄球菌在CTCL中。发病。我们将从CTCL患者的皮肤中分离，序列和研究S.金黄色葡萄球菌（来自肿瘤部位和不受影响的皮肤），确定这些菌株产生的毒素和垂体的曲目。我们预计CTCL相关的分离株在产生大量下垂的能力上会有所不同每个生物体的类型及其SAG基因含量的分布。我们将使用体外方法来评估 CTCL患者皮肤菌群产生的脱落和其他毒素和脱蛋白有助于T细胞激活，增殖和恶性转化。进一步了解金黄色葡萄球菌对CTCL发病机理的贡献并证明了因果关系金黄色葡萄球菌定植与恶性疾病之间的联系，我们将使用我们的新动物模型以及我们的无菌设施，以检查微生物暴露对CTCL启动和进展的影响。我们还将利用尖端的单细胞，高通量技术，同时实现表面表现，T细胞受体基因重排和转录组学的分析以实现 CTCL中肿瘤微环境的前所未有的分辨率，并检查金黄色葡萄球菌定殖的微环境。我们的提案中概述的研究将为CTCL发病机理提供重大见解，并将告知与当前的化学治疗相比，未来疗法的开发更具针对性和毒性方法。