Pathogenesis of Acute Respiratory Diseases: SARS and INFLUENZA

流感、SARS、汉塔和埃博拉病毒感染后高发病率和高死亡率的因素 包括强劲细胞因子产生(细胞因子风暴)、过度炎症渗透(免疫病理学) 以及病毒引起的组织破坏。我们对致病性人H1N1流感病毒的研究(细胞146， 2011年；PNAS 108,2011)首次明确表明细胞因子风暴是由细胞因子风暴引起的，而不是与 以及由此导致的发病率和死亡率。感染发生在上皮细胞，细胞因子风暴开始并 由肺内皮细胞扩增。鞘氨醇-1-磷酸(S1P)1受体对血管内皮细胞的调节作用 肺内皮细胞抑制早期先天免疫反应保护受感染宿主 在联合使用抗病毒治疗的情况下，显著优于抗病毒化合物(82%)(50%)。 S1P激动剂提供最佳保护(96%)。我们证明了细胞因子的产生和白细胞 募集是独立发生的，S1P1受体信号转导于肺内皮细胞 监管这两个事件。我们发现细胞因子的放大依赖于1型干扰素信号。这个 MRCE收集了对先天性免疫途径和类型感兴趣和有经验的研究人员 1干扰素信号与我们的建议具有协同作用。我们的目标是了解细胞因子是如何 扩增是受调控的。具体地说，1型干扰素是如何调节以下全局细胞因子放大的 人类大流行H1N1/2009流感感染。我们将确定是否存在类似的放大环路 初步证据表明，S1P疗法成功地改善了SARS感染。我们的特定 AIMS利用现有试剂确定需要扩增的干扰素亚群(S) 早期细胞因子的产生，谱系追踪报告TD-番茄和IFNAR1 FLOX/FLOX小鼠来鉴定 负责细胞因子放大的特定细胞亚群，并分析串扰信号通路 是细胞因子风暴中的重要参与者。我们未来的研究成果是针对这两种疗法 控制细胞因子风暴和标志物，以确定这些疾病的易感个体。

Factors implicated in high morbidity and mortality following influenza, SARS, Hanta and Ebola virus infection include robust cytokine production (cytokine storm), excessive inflammatory infiltrates (immunopathology), and virus-induced tissue destruction. Our studies with pathogenic human H1N1 influenza virus (Cell 146, 2011; PNAS 108, 2011) were the first to definitively show that cytokine storm causes, rather than associates with resultant morbidity and mortality. Infection occurs in epithelial cells and cytokine storm is initiated and amplified by pulmonary endothelial cells. Modulation of sphingosine-1-phosphate (S1P)1 receptor on pulmonary endothelial cells curtails early innate immune responses and protects the infected host significantly better (82%) than antiviral compounds (50%) while usage of antiviral therapy combined with S1P agonists afford optimal protection (96%). We demonstrated that cytokine production and leukocyte recruitment are independent occurrences, and S1P1 receptor signaling on pulmonary endothelial cells regulates both events. We uncovered that cytokine amplification depends on type 1 interferon signaling. The MRCE with its collection of investigators with interests and experience in innate immune pathways and type 1 interferon signaling provide a synergism with our proposal. Our goal is to understand how cytokine amplification is regulated. Specifically, how type 1 interferon regulates global cytokine amplification following human pandemic H1N1/2009 influenza infection. We will determine if a similar amplification loop exists in SARS infection for which preliminary evidence shows is successfully modified by S1P therapy. Our specific aims make use of currently on hand reagents to determine the subset(s) of interferon required to amplify early cytokine production, lineage tracing reporter Td-tomato and IFNAR1flox/flox mice to identify the specific cell subsets responsible for cytokine amplification and to analyze cross talk signaling pathways that are important players in cytokine storm. The future fruits of our studies are aimed at both therapeutics to control cytokine storm and markers to identify susceptible individuals to these diseases.