Host Response in S. aureus Infections: Role of T cells

金黄色葡萄球菌感染中的宿主反应：T 细胞的作用

• 批准号: 6888965
• 负责人: ARTHUR O TZIANABOS
• 金额: $ 37.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6888965
• 关键词: Staphylococcus aureus; Staphylococcus infection; amino group; antigen antibody reaction; bacteria infection mechanism; bacterial capsules; cell migration; chemokine; gene targeting; genetically modified animals; helper T lymphocyte; host organism interaction; laboratory mouse; leukocyte activation /transformation; molecular cloning; neutrophil; nuclear magnetic resonance spectroscopy; tissue /cell culture

DESCRIPTION (provided by applicant): Staphylococcus aureus is an opportunistic bacterial pathogen responsible for a diverse spectrum of human and animal diseases, including wound infections, osteomyelitis, endocarditis, and bacteremia leading to secondary abscesses in any of the major organ systems. Staphylococcal infections occur most frequently when mucosal barriers are breached, following insertion of a foreign body, or in the presence of other factors that compromise the immune system of the host. Currently, the host response to this organism is poorly understood. The majority of studies to date have focused on the role of PMNs modulating the host response to staphylococcal infections. S. aureus is typically classified as an extracellular pathogen that does not directly interact with the host immune system via T cells. However, we have shown that the staphylococcus produces a capsule with both free amino and negatively charged carboxyl groups that mediates its pathogenic potential in an experimental model of intraabdominal abscess formation in a T cell-dependent manner. This capsule can activate CD4+ T cells and induce the production of CXC chemokines, peptides that activate and recruit PMNs to sites of inflammation. The transfer of CD4+ T cells that have been activated by the S. aureus capsule promotes abscess formation in naive recipient animals. Based on these data, we hypothesize that CD4+ T cells activated by S. aureus capsules are critical in determining the outcome of staphylococcal infections through the release of CXC chemokines that control PMN trafficking to infected sites. This hypothesis will be tested in staphylococcal animal models of subcutaneous abscess formation and surgical wound infection. These models are clinically relevant, low-inoculum murine models of staphylococcal disease that mimic important aspects of human disease. We propose to: 1) Characterize the mechanism by which S. aureus synthesizes a capsule with a zwitterionic charge motif; 2) Evaluate the role of the capsular polysaccharide in the interaction between S. aureus and the host; 3) Determine the role of T cells in the pathogenesis of and host response to staphylococcal infections; and 4) Characterize the T cell-mediated CXC chemokine response to S. aureus infection and its role in regulation of PMN trafficking. Results from the proposed studies should provide insight regarding the under appreciated role of T cells in the pathogenesis and host response in S. aureus infections. This information may reveal new strategies for the prevention or treatment of S. aureus infections through immunomodulation of the host response to this organism.

描述（由申请人提供）：金黄色葡萄球菌是一种机会性细菌病原体，可引起多种人类和动物疾病，包括伤口感染、骨髓炎、心内膜炎和菌血症，导致任何主要器官系统继发性脓肿。当粘膜屏障被破坏、插入异物或存在其他损害宿主免疫系统的因素时，葡萄球菌感染最常发生。目前，宿主对该生物体的反应知之甚少。迄今为止，大多数研究都集中在中性粒细胞调节宿主对葡萄球菌感染反应的作用。金黄色葡萄球菌通常被归类为细胞外病原体，不会通过 T 细胞直接与宿主免疫系统相互作用。然而，我们已经证明，葡萄球菌产生一种含有游离氨基和带负电荷的羧基的荚膜，在腹内脓肿形成的实验模型中以 T 细胞依赖性方式介导其致病潜力。这种胶囊可以激活 CD4+ T 细胞并诱导 CXC 趋化因子的产生，CXC 是一种肽，可激活 PMN 并将其招募到炎症部位。已被金黄色葡萄球菌荚膜激活的 CD4+ T 细胞的转移促进了幼稚受体动物中脓肿的形成。基于这些数据，我们假设金黄色葡萄球菌胶囊激活的 CD4+ T 细胞通过释放控制 PMN 运输到感染部位的 CXC 趋化因子，对于确定葡萄球菌感染的结果至关重要。这一假设将在皮下脓肿形成和手术伤口感染的葡萄球菌动物模型中得到检验。这些模型是临床相关的葡萄球菌疾病的低接种量鼠模型，模拟了人类疾病的重要方面。我们建议：1）表征金黄色葡萄球菌合成具有两性离子电荷基序的胶囊的机制； 2）评价荚膜多糖在金黄色葡萄球菌与宿主相互作用中的作用； 3）确定T细胞在葡萄球菌感染发病机制和宿主反应中的作用； 4) 表征 T 细胞介导的 CXC 趋化因子对金黄色葡萄球菌感染的反应及其在调节 PMN 运输中的作用。拟议研究的结果应有助于深入了解 T 细胞在金黄色葡萄球菌感染的发病机制和宿主反应中的作用。该信息可能揭示通过免疫调节宿主对该生物体的反应来预防或治疗金黄色葡萄球菌感染的新策略。