Project 4: Role of Antecedent Influenza Infection in Severity and Outcome of Hemorrhagic MRSA Pneumonia

项目 4：既往流感感染对出血性 MRSA 肺炎严重程度和结果的影响

• 批准号: 9282596
• 负责人: Tanyalak Parimon
• 金额: $ 27.02万
• 依托单位: IDAHO VETERANS RESEARCH / EDUCATION FDN
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9282596
• 关键词: Adherence; Alveolar; Animal Model; Antibiotics; Bacterial Adhesins; Bacterial Pneumonia; Basic Science; Biomedical Research; Blood Platelets; Blood capillaries; Cause of Death; Cell Surface Receptors; Cell membrane; Cells; Cellular Structures; Characteristics; Cleaved cell; Clinical; Coculture Techniques; Communicable Diseases; Communities; Complex; Deposition; Disease; Edema; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Exotoxins; Future; Glycoproteins; Guidelines; Health; Hemolysin; Hemorrhage; Human; Idaho; In Vitro; Infection; Infectious Diseases Research; Influenza; Influenza A virus; Life; Lung; Measures; Mediating; Modeling; Molecular; Necrosis; Neuraminidase; Neuraminidase inhibitor; Oseltamivir; Outcome; Pathogenesis; Pathogenicity; Patients; Peptide Hydrolases; Perfusion; Physicians; Platelet aggregation; Pneumonia; Process; Pulmonology; Recommendation; Role; Scientist; Severities; Sialic Acids; Signal Transduction; Soft Tissue Infections; Staphylococcus aureus; Structure; Symptoms; System; Testing; Therapeutic; Tissues; Viral; Virulence Factors; Virus Diseases; Whole Blood; capillary; co-infection; fluidity; improved; improved outcome; in vivo; inhibitor/antagonist; insight; methicillin resistant Staphylococcus aureus; mortality; mouse model; multidisciplinary; neutrophil; pandemic influenza; programs; receptor; synergism; virology

Project 4 - SUMMARY Background: Secondary bacterial pneumonia caused by community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) is the leading cause of death in patients following influenza A virus (IAV) infection. How IAV predisposes to severe CA-MRSA pneumonia is not fully understood. Hypothesis: We hypothesize that that a lethal synergism exists between influenza A neuraminidase (iNA) and S. aureus alpha- hemolysin (AH) that contributes to widespread lung destruction characteristic of this infection and that targeting the mechanism responsible for this synergy could lessen severity and improve outcomes in patients with post- influenza hemorrhagic necrotizing CA-MRSA pneumonia. Specific Aim 1: To determine the molecular mechanism whereby iNA augments AH-induced alveolo-capillary barrier destruction. For this, AH-induced ADAM10 protease activity in cultured pulmonary epithelial cells will be correlated with epithelial cell barrier structure and function in the presence and absence of iNA treatment. Specific Aim 2: To elucidate the role of iNA in priming the pulmonary microvascular endothelium for increased AH-induced platelet-neutrophil aggregate (PNA) deposition. PNAs contribute to tissue destruction in many soft tissue infections. We have shown that AH is the sole S. aureus exotoxin that mediates formation of PNA in human whole blood. To determine whether iNA augments this process, we will measure AH-induced PNA formation in whole blood and in the presence of pulmonary microvascular endothelial cells under static vs flow conditions with and without iNA treatment. Specific Aim 3. To assess the in vivo efficacy of an iNA inhibitor in decreasing the mortality associated with experimental post-influenza CA-MRSA pneumonia. Contrary to the current guidelines, we have shown the value of early anti-viral therapy, given alone, in improving outcome of experimental post- influenza MRSA pneumonia, whereas typical anti-MRSA antibiotics given alone were not efficacious. Using this model, we will investigate the mechanisms that underlay the efficacy of early vs late oseltamivir treatment (an iNA inhibitor), alone and together with antibiotics, in reducing lung destruction and improving outcome in post-influenza MRSA pneumonia. Impact on Human Health: Together, results from these studies may signal a paradigm shift in the current approach to treatment of post-influenza MRSA pneumonia. Contribution to Multi-disciplinary Infectious Diseases Research Program: Dr. Parimon blends clinical expertise in pulmonary medicine with a basic science understanding of the mechanisms of pathogenesis of severe bacterial pneumonia. Studies described in this proposal will increase the core's expertise pathogenic virology especially as it relates to post-influenza MRSA pneumonia. Because other bacterial soft tissue infections are purportedly made worse by antecedent viral infection, results from this study could be broadly applicable to several life-threatening diseases.

项目4-摘要 背景：由社区获得的甲氧西林抗性引起的次生细菌性肺炎 金黄色葡萄球菌（CA-MRSA）是流感病毒（IAV）患者的主要死亡原因 感染。 IAV易于易于易于易肺炎。假设：我们 假设流感A神经氨酸酶（INA）和金黄色葡萄球菌α-存在致命的协同作用 血素（AH）有助于这种感染的广泛肺破坏特征和靶向 负责这种协同作用的机制可以降低严重程度并改善后患者的结局 流感出血性坏死性CA-MRSA肺炎。特定目标1：确定分子 INA增强AH引起的肺泡毛细管屏障破坏的机制。为此，AH引起的 培养的肺上皮细胞中的ADAM10蛋白酶活性将与上皮细胞屏障相关 在存在和不存在INA处理的情况下结构和功能。特定目标2：阐明 INA启动肺微血管内皮，以增加AH诱导的血小板中性嗜性 骨料（PNA）沉积。 PNA有助于许多软组织感染的组织破坏。我们有 表明AH是唯一的金黄色葡萄球菌外毒素，它介导了人类全血PNA的形成。到 确定INA是否增加了此过程，我们将测量AH诱导的全血PNA形成，并且 在静态与流动条件下，有和没有的静态微血管内皮细胞存在 INA治疗。特定目的3。评估INA抑制剂降低死亡率的体内功效 与实验后的Influenza CA-MRSA肺炎有关。与当前的准则相反，我们 已经显示出单独给出的早期抗病毒疗法的价值，以改善实验后的结果 流感MRSA肺炎，而单独给出的典型抗MRSA抗生素没有有效。使用 该模型，我们将调查下降早期与晚期oseltamivir处理功效的机制 （一种INA抑制剂），独自与抗生素一起减少肺部破坏并改善结果 炎后MRSA肺炎。对人类健康的影响：总之，这些研究的结果可能会发出信号 当前治疗Influenza MRSA肺炎的方法的范式转移。对 多学科传染病研究计划：Parimon博士融合了临床专业知识 肺部医学具有基础科学的理解，对严重的发病机理 细菌性肺炎。该提案中描述的研究将增加核心的专业知识致病病毒学 特别是与Influenza MRSA肺炎有关。因为其他细菌软组织感染是 据称因先前病毒感染而变得更糟，这项研究的结果可能广泛适用于 几种威胁生命的疾病。