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

• 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
• 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' 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

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 (CTCL) 是一组异质性血液相关癌症，其特征是 由慢性炎症和皮肤中恶性 T 细胞的积累引起。在淋巴瘤中，CTCL是 其独特之处在于转化细胞具有显着的向真皮性——接触微生物可能会 有助于疾病病因学。 CTCL 患者经常死于细菌感染，两者之间存在相关性 已观察到某些金黄色葡萄球菌菌株的存在和疾病的严重程度。 共生菌和病原菌可以影响幼稚 T 淋巴细胞的分化，引发增殖 并通过产生超级抗原 (SAgs) 来激活 T 细胞，并产生许可性 通过影响趋化因子和细胞因子的表达来改变肿瘤细胞的微环境。我们假设， 以及个体的遗传倾向和 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由这种病原体的某些菌株产生的 SAgs 会促进恶性 CTCL 中的转化和克隆进化。 其他小组之前的研究和我们的初步研究表明金黄色葡萄球菌特别与 CTCL 相关 发病。我们将从 CTCL 患者的皮肤中分离、测序和研究金黄色葡萄球菌分离株（来自 肿瘤部位和未受影响的皮肤）并确定这些菌株产生的毒素和 SAgs 的所有成分。 我们预计 CTCL 相关分离株在产生大量 SAg 的能力方面会有所不同 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如何 CTCL 患者皮肤微生物群产生的 SAgs 和其他毒素和外蛋白有助于 T 细胞 活化、增殖和恶性转化。 进一步了解金黄色葡萄球菌对 CTCL 发病机制的贡献并证明因果关系 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 CTCL 动物模型 我们的无菌设施用于检查微生物暴露对 CTCL 发生和进展的影响。我们 还将利用尖端、单细胞、高通量技术，实现同时 分析表面表位、T细胞受体基因重排和转录组学以实现 CTCL 中肿瘤微环境的前所未有的分辨率并检查 金黄色葡萄球菌定植时的微环境。 我们提案中概述的研究将为 CTCL 发病机制提供重要的见解，并将提供信息 开发比当前化疗更有针对性且毒性更小的未来疗法 接近。