Cellular and molecular mechanisms controlling sepsis-induced immunoparalyses state

项目总结/摘要 脓毒症被定义为由宿主对感染的反应失调引起的危及生命的器官功能障碍。它 每年有170万美国人面临巨大的公共卫生负担（死亡率为20-25%）。在 通常，脓毒症的早期阶段的特征在于潜在有害的高度炎症状态。 然而，在脓毒症的细胞因子风暴期存活的患者进入免疫麻痹状态， 感染易感性增强，病毒再激活，以及脓毒症后数年的死亡率。脓毒症诱导 淋巴细胞减少减少免疫细胞的数量并影响剩余/存活细胞的功能。 然而，脓毒症引起的淋巴细胞减少是短暂的，而长期的免疫麻痹（或 免疫抑制）的发展（即使在淋巴细胞数量正常化后），现在被认为是一个主要的 对细菌和病毒病原体敏感性增加的时间延长的原因通常由 健康个体的免疫系统。因此，我们的长期目标是精确确定，在细胞上， 和分子水平，脓毒症诱导的各种淋巴细胞群的变化，支持和定义了 免疫麻痹的慢性状态和免疫细胞不能适当地发挥其效应功能。我们 确定了四个相互关联的研究领域，我们将追求：a）探索分子机制， 控制感染或疫苗诱导的保护性记忆CD 8 T细胞的长期维持和功能 B）确定对肿瘤发展的易感性增加的细胞基础， 在脓毒症幸存者中引起自身免疫反应的能力降低; c）开发新的实验模型， 脓毒症研究; d）调查临床（人）和实验（小鼠）研究之间的相互作用， 阐明控制脓毒症诱导的免疫麻痹状态的机制和途径。处理这些关键 我们对脓毒症诱导的免疫麻痹的理解的差距将最终发现新的靶点， 用于开发更好，更有效的治疗败血症幸存者。

Project Summary/Abstract Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It represents a significant public health burden striking 1.7 million American annually (with 20-25% mortality). In general, early stages of sepsis are characterized by a potentially detrimental hyperinflammatory state. However, patients who survive the cytokine storm phase of sepsis enter a state of immunoparalysis defined by enhanced susceptibility to infection, viral reactivation, and mortality years after the septic insult. Sepsis-induced lymphopenia reduces the number of immune cells and influences the function of remaining/surviving cells. Yet, the sepsis-induced lymphopenia is transient while the prolonged immunoparalysis (or immunosuppression) that develops (even after lymphocyte numbers normalize) is now considered a leading reason for the extended period of increased susceptibility to bacterial and viral pathogens normally handled by the immune system in healthy individuals. Therefore, our long-term goal is to precisely determine, on cellular and molecular levels, sepsis-induced changes in various lymphocyte populations that support and define the chronic state of immunoparalysis and inability of immune cells to exert their effector functions properly. We identified four interconnected areas of research that we will pursue: a) Explore molecular mechanisms that govern long-term maintenance and function of infection-or vaccine-induced protective memory CD8 T cell responses after sepsis; b) Define the cellular basis of increased susceptibility to tumor development and decreased ability to evoke autoimmune responses in sepsis survivors; c) Develop new experimental models of sepsis research; d) Investigate the interplay between clinical (human) and experimental (mouse) research to elucidate mechanisms and pathways that control sepsis-induced immunoparalysis state. Addressing these key gaps in our understanding of sepsis-induced immunoparalysis will ultimately uncover new targets that can be used to develop better and more efficient treatments of sepsis survivors.