Regulation of Host Response in S. pneumoniae Infections

肺炎链球菌感染中宿主反应的调节

• 批准号: 7588501
• 负责人: Jian-Dong Li
• 金额: $ 37.81万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588501
• 关键词: Acute; Adverse effects; Affect; Alveolar; Antibiotics; Bacteria; Basic Science; Cells; Data; Development; Dominant-Negative Mutation; Foundations; Hemorrhage; Hospitalization; Human; Immune; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Lead; Lung; MAP Kinase Gene; MAPK14 gene; Meningitis; Molecular; Morbidity - disease rate; Mus; NF-kappa B; Otitis Media; Pathway interactions; Patients; Plasminogen Activator Inhibitor 1; Play; Pneumococcal Infections; Pneumonia; Publishing; Regulation; Role; Signal Transduction; Sinusitis; Small Interfering RNA; Solid; Staging; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; Therapeutic; Therapeutic Agents; Translating; Tumor Suppressor Proteins; Up-Regulation; Virulence Factors; base; clinical application; clinically significant; in vivo; insight; mortality; new therapeutic target; novel; novel therapeutics; pathogen; protective effect; skills; therapeutic target

Streptococcus pneumoniae (S.p.), an important human pathogen causing pneumonia, is a major cause of morbidity and mortality worldwide. Its early mortality rate still remains the highest when compared to the pre-antibiotic era. Pneumolysin (PLY), a key cytolytic virulence factor, plays an important role in inducing acute alveolar hemorrhage and early lethality in severe S.p. infection. However, little is known about the underlying molecular mechanisms. Our Long-term objective is to fully understand the molecular mechanisms by which S.p. PLY-induced early lethality is caused and regulated in severe S.p. infections so that effective therapeutic strategy can be developed. Recently our published preliminary data indicate that tumor suppressor CYLD deficiency protects mice against S.p. PLY-induced alveolar hemorrhage and early lethality (Lim et al, Immunity, 2007). We also found that CYLD inhibits MKK3-p38-dependent type 1 plasminogen activator inhibitor (PAI1) expression in lung, thereby potentiating alveolar hemorrhage and early lethality. Of particular clinical significance is the direct evidence for the efficacy of the exogenous administration of PAI-1 in reducing alveolar hemorrhage and early lethality without serious adverse effects. These encouraging results have thus laid a solid foundation for us to further investigate the molecular mechanisms by which CYLD potentiates S.p. PLY-induced alveolar hemorrhage and early lethality via inhibition of MKK3-p38 -dependent PAI-1 expression (Hypothesis & Short-term Objective). Aim 1: Determine the molecular mechanism by which CYLD-deficiency protects mice against S.p. PLY-induced alveolar hemorrhage and early lethality via enhancing PAI-1 and the contribution of PAI-1 to the immune/inflammatory responses against S.p. Aim 2: Determine the molecular mechanism by which CYLD-deficiency protects mice against S.p. PLY-induced alveolar hemorrhage and early lethality via MKK3-p38-dependent up-regulation of PAI-1 expression. The proposed studies will provide novel insights into the molecular mechanisms underlying alveolar hemorrhage and lethality during early stage of severe S.p. infections and will lead to development of novel therapeutic agent for treating severe S.p. infections. Overall, the proposed studies will not only accelerate our scientific discovery and help further translate these discoveries from the basic science to clinical application, but will also contribute significantly to stimulating the economy by enabling hiring of additional professional and technical staff with needed expertise's and skills.

肺炎链球菌（S.p.）是引起肺炎的重要人类病原体，是全世界发病和死亡的主要原因。与抗生素出现之前的时代相比，其早期死亡率仍然是最高的。肺炎球菌溶血素 (PLY) 是一种关键的溶细胞毒力因子，在诱导重症肺炎球菌急性肺泡出血和早期致死方面发挥着重要作用。感染。然而，人们对潜在的分子机制知之甚少。我们的长期目标是充分了解 S.p. 的分子机制。 PLY 诱导的早期致死是在严重的 S.p. 中引起和调节的。感染，以便制定有效的治疗策略。最近我们发表的初步数据表明，肿瘤抑制因子 CYLD 缺陷可以保护小鼠免受 S.p. 感染。 PLY 诱导的肺泡出血和早期致死（Lim 等人，Immunity，2007）。我们还发现，CYLD 抑制肺部 MKK3-p38 依赖性 1 型纤溶酶原激活剂抑制剂 (PAI1) 的表达，从而加剧肺泡出血和早期致死率。具有特殊临床意义的是外源性施用 PAI-1 在减少肺泡出血和早期致死率方面的功效且无严重副作用的直接证据。这些令人鼓舞的结果为我们进一步研究CYLD增强S.p.的分子机制奠定了坚实的基础。 PLY 通过抑制 MKK3-p38 依赖性 PAI-1 表达诱导肺泡出血和早期致死（假设和短期目标）。目标 1：确定 CYLD 缺陷保护小鼠免受链球菌感染的分子机制。 PLY 通过增强 PAI-1 诱导肺泡出血和早期致死，以及 PAI-1 对 S.p. 免疫/炎症反应的贡献。目标 2：确定 CYLD 缺陷保护小鼠免受链球菌感染的分子机制。 PLY 通过 MKK3-p38 依赖性上调 PAI-1 表达诱导肺泡出血和早期致死。拟议的研究将为严重肺炎球菌早期肺泡出血和致死的分子机制提供新的见解。感染，并将导致治疗严重肺炎球菌感染的新型治疗剂的开发。感染。总体而言，拟议的研究不仅将加速我们的科学发现并帮助进一步将这些发现从基础科学转化为临床应用，而且还将通过雇用更多具有所需专业知识和技能的专业和技术人员来为刺激经济做出重大贡献。