Regulation of Host Response in S. pneumoniae Infections

肺炎链球菌（链球菌）是引起肺炎的重要人类病原体，是世界范围内发病率和死亡率的主要原因。与前抗生素时代相比，它的早期死亡率仍然是最高的。溶血素（pneumolyysin， PLY）是一种关键的毒力因子，在严重S.p.感染的急性肺泡出血和早期死亡中起重要作用。然而，人们对其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.p ly诱导的早期死亡在严重s.p.p感染中引起和调节的分子机制，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缺乏可保护小鼠免受s.p.p ply诱导的肺泡出血和早期死亡（Lim et al, Immunity, 2007）。我们还发现CYLD抑制mkk3 -p38依赖性1型纤溶酶原激活物抑制剂（PAI1）在肺中的表达，从而增强肺泡出血和早期死亡。特别具有临床意义的是直接证明外源性给药PAI-1在减少肺泡出血和早期致死率方面的疗效，且无严重不良反应。这些令人鼓舞的结果为我们进一步研究CYLD通过抑制MKK3-p38依赖性PAI-1表达而增强s.p.p ly诱导的肺泡出血和早期死亡的分子机制奠定了坚实的基础（假设&短期目标）。目的1：确定cyld缺乏症通过增强PAI-1和PAI-1对sp免疫/炎症反应的贡献，保护小鼠免受sp - ply诱导的肺泡出血和早期死亡的分子机制。目的2：确定cyld缺乏症通过mkk3 -p38依赖性上调PAI-1表达，保护小鼠免受sp - ply诱导的肺泡出血和早期死亡的分子机制。这些研究将为严重S.p.感染早期肺泡出血和致死性的分子机制提供新的见解，并将导致治疗严重S.p.感染的新药物的开发。总的来说，拟议的研究不仅将加速我们的科学发现，并有助于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技术人员，对刺激经济做出重大贡献。

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.