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认为是超抗原（SAg），因为它是 不像常规肽那样加工，是一种非常强大的T细胞刺激剂。肠毒素会导致 致死性中毒性休克和故意暴露于S.金黄色葡萄球菌肠毒素有可能 使大批人丧失能力。这种生物攻击的后果可能导致严重的 呼吸道疾病的风险。尽管如此，人类患者的某些肺部疾病 最近已经与SAg的存在，以及SAg在T细胞中的刺激有关。 呼吸道驱动炎性级联反应，导致肺中的严重病理结果。这 包括肺部炎症、血管渗透性和肺泡炎。虽然这种致病反应 涉及SAg特异性T细胞、疾病起始的潜在机制和肺炎症介质， 炎症不清楚。我们的数据表明，先天性细胞的募集和它们在肺中的激活是 依赖于携带TCRVp的T细胞，并且在暴露后迅速发生。一项新的发现清楚地表明， 这证明了这一点，因为吸入SAg后仅几小时，γ ST细胞开始合成IL-17 α。 出乎意料的是，IL-I7 a的产生显示依赖于TCR Vp T细胞的存在。的作用 将在目标1中研究参与控制Y 5 T细胞活化的SAg特异性IT细胞亚群的数量。 早期先天性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细胞内蛋白质， 细胞在目标2中，我们将纯化和表征我们在大肠杆菌中检测到的蛋白酶敏感因子。 支气管肺泡灌洗液，其具有DAMP的特征。我们的目标是鉴定这种分子， 通过定义其细胞靶点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活性的结果是炎症的加剧，在这方面，我们的新数据显示， IL-33通路的潜在作用。目标3将测试S。金黄色葡萄球菌肠毒素吸入对IL-33的影响 途径以及是否可以对其进行调节以制定针对肺危象的对策。 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， 这些蛋白质在诱导非常强的免疫应答中发挥作用。这些蛋白质的性质使得T 细胞的反应强烈，这可能导致严重的疾病的人，没有明确的治疗。 本提案将解决以理解这些反应的启动为中心的重要问题。