Impact of Staphylococcus Aureus enterotoxin on pulmonary inflamation

金黄色葡萄球菌肠毒素对肺部炎症的影响

• 批准号: 8424005
• 负责人: Anthony T Vella
• 金额: $ 38.33万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424005
• 关键词: Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Aerosols; Alveolitis; Area; Biological; Breathing; Bronchoalveolar Lavage Fluid; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Data; Disease; Distress; Enterotoxins; Goals; Hour; Human; Immune response; Individual; Inflammation; Inflammatory; Injury; Instruction; Lead; Lung; Lung Inflammation; Lung diseases; Mediator of activation protein; Mining; Mus; Nature; Outcome; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Play; Pneumonia; Population; Process; Production; Property; Proteins; Proteomics; Research; Respiratory System; Respiratory tract structure; Role; Shock; Signal Transduction; Staging; Staphylococcus aureus; Structure; Superantigens; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Toxic Shock Syndrome; United States National Institutes of Health; Vascular Permeabilities; biodefense; cellular targeting; cytokine; microbial; pathogen; respiratory; response; weapons

The biodefense agent Staphylococcus aureus enterotoxin is regarded as a superantigen (SAg) because it is not processed as conventional peptide and is an incredibly powerful T cell stimulant. Enterotoxins can cause lethal toxic shock in humans and intentional aerosol exposure of S. aureus enterotoxin has the potential to incapacitate large groups of people. The consequences of such a biological attack can lead to severe respiratory illness in exposed individuals. Notwithstanding, certain pulmonary diseases in human patients have recently been associated with the presence of SAg, and stimulation of T cells with SAg in the respiratory tract drives an inflammatory cascade resulting in severe pathological outcomes in the lung. This includes pulmonary inflammation, vascular permeability and alveolitis. Although this pathogenic response involves SAg-specific T cells, the underlying mechanism of disease initiation and mediators of lung inflammation are unclear. Our data show that innate cell recruitment and their activation in lung are dependent upon TCR Vp bearing T cells and occurs rapidly after exposure. A new finding clearly demonstrates this point since only a few hours after SAg inhalation y.ST cells begin to synthesize I L-17a. Unexpectedly, 1L-I7a production was shown to be dependent on the presence of TCR Vp T cells. The role of SAg-specific IT cell sub-populations involved in controlling Y 5 T cell activation will be investigated in Aim 1. A consequence of early innate cell activation is pulmonary tissue injury, and by proteomic mining of bronchoalveolar lavage fluid we detected intracellular proteins that may have come from damaged lung cells. In Aim 2 we will purify and characterize a protease-sensitive factor that we detected in bronchoalveolar lavage fluid which has characteristics of a DAMP. Our goal is to identify this molecule and validate its ability to stimulate cytokine release by defining its cellular target and signaling properties. Lastly, an outcome of DAMP activity is intensification of inflammation, and in this regard our new data show a potential role for the IL-33 pathway. Aim 3 will test how S. aureus enterotoxin inhalation impacts the IL-33 pathway and if it can be modulated to develop countermeasures against a pulmonary crisis. RELEVANCE (See instructions): The study of enterotoxins released from Staphylococcus aureus is an important area of research due to the role these proteins play in inducing very strong immune responses. The nature ofthese proteins allows T cells to respondlvigorously which can lead to serious illness in people for which there is no clear treatment. This proposal will address important issues centered on understanding the initiation of these responses.

生物防御剂金黄色葡萄球菌肠毒素被视为超级抗原 (SAg)，因为它 不以传统肽的方式加工，而是一种极其强大的 T 细胞兴奋剂。肠毒素可引起 人类致命的中毒性休克和故意气溶胶接触金黄色葡萄球菌肠毒素有可能 使大批人丧失行动能力。这种生物攻击的后果可能会导致严重的后果 接触者出现呼吸道疾病。尽管如此，人类患者的某些肺部疾病 最近发现与 SAg 的存在以及 SAg 刺激 T 细胞有关 呼吸道驱动炎症级联反应，导致肺部严重病理结果。这 包括肺部炎症、血管通透性和肺泡炎。尽管这种致病反应 涉及 SAg 特异性 T 细胞、疾病发生的潜在机制和肺部介质 炎症情况不清楚。我们的数据表明，肺中的先天细胞募集及其激活是 依赖于带有 TCR Vp 的 T 细胞，并且在暴露后迅速发生。明确的新发现 证明了这一点，因为仅在 SAg 吸入后几个小时，y.ST 细胞就开始合成 I L-17a。 出乎意料的是，1L-I7a 的产生取决于 TCR Vp T 细胞的存在。角色 目标 1 将研究参与控制 Y 5 T 细胞激活的 SAg 特异性 IT 细胞亚群。 早期先天细胞激活的结果是肺组织损伤，并且通过蛋白质组学挖掘 我们在支气管肺泡灌洗液中检测到可能来自受损肺的细胞内蛋白质 细胞。在目标 2 中，我们将纯化并表征我们在中检测到的蛋白酶敏感因子 支气管肺泡灌洗液，具有 DAMP 的特性。我们的目标是识别这个分子并 通过定义其细胞靶标和信号传导特性来验证其刺激细胞因子释放的能力。最后， DAMP 活性的一个结果是炎症加剧，在这方面，我们的新数据显示 IL-33 途径的潜在作用。目标 3 将测试吸入金黄色葡萄球菌肠毒素如何影响 IL-33 途径以及是否可以对其进行调节以制定针对肺部危机的对策。 相关性（参见说明）： 金黄色葡萄球菌释放的肠毒素的研究是一个重要的研究领域，因为 这些蛋白质在诱导非常强的免疫反应中发挥着重要作用。这些蛋白质的性质允许 T 细胞做出强烈反应，这可能会导致人们患上严重疾病，而目前尚无明确的治疗方法。 该提案将解决以理解这些响应的启动为中心的重要问题。