Regulation of Host Response in S. pneumoniae Infections

肺炎链球菌（S. p.），一种引起肺炎的重要人类病原体，是全世界发病率和死亡率的主要原因。与前抗生素时代相比，其早期死亡率仍然是最高的。链球菌溶血素（acetylolysin，ac然而，对潜在的分子机制知之甚少。我们的长期目标是充分了解在严重的S. p.感染中S. p. PLY诱导的早期致死性的分子机制，以便开发有效的治疗策略。最近，我们发表的初步数据表明，肿瘤抑制因子CYLD缺陷保护小鼠免受S. p. PLY诱导的肺泡出血和早期致死（Lim等人，Immunity，2007）。我们还发现CYLD抑制肺中MKK 3-p38依赖的1型纤溶酶原激活物抑制剂（PAI 1）的表达，从而增强肺泡出血和早期致死性。具有特别临床意义的是派-1的外源性施用在减少肺泡出血和早期致死性而没有严重副作用方面的功效的直接证据。这些令人鼓舞的结果为我们进一步研究CYLD通过抑制MKK 3-p38依赖的派-1表达而增强S. p. PLY诱导的肺泡出血和早期致死的分子机制奠定了坚实的基础（假说和短期目标）。目标1：确定CYLD缺乏通过增强派-1和派-1对针对S. p. PLY的免疫/炎症应答的贡献来保护小鼠免受S. p. PLY诱导的肺泡出血和早期致死的分子机制目的2：确定CYLD缺陷通过MKK 3-p38依赖性派-1上调保护小鼠免受S. p. PLY诱导的肺泡出血和早期致死的分子机制。1表达式。拟议的研究将提供新的见解肺泡出血和致命性的分子机制在早期阶段的严重的S. p.感染，并将导致开发新的治疗药物治疗严重的S. p.感染。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和技术人员，为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.