CD4 T cell dysfunction and reprogramming during sepsis

脓毒症期间 CD4 T 细胞功能障碍和重编程

• 批准号: 10633073
• 负责人: Thomas S Griffith
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633073
• 关键词: Activities of Daily Living; Acute; Address; Adult; Affect; American; Area; Back; CD4 Positive T Lymphocytes; Cause of Death; Cell Compartmentation; Cells; Cellular Immunity; Cellular biology; Cessation of life; Childhood; Chronic; Exposure to; Functional disorder; Future; Genomics; Goals; Healthcare Industry; Human; Human Biology; Immune; Immune response; Immune system; Immunosuppression; Impairment; Incidence; Infection; Inflammatory; Interferon Type II; Interleukin-1 beta; Interleukin-6; Intervention; Investigation; Knowledge; Laboratory mice; Life; Modeling; Molecular; Mus; Nosocomial Infections; Organ; Patients; Phase; Play; Population; Predisposition; Proteomics; Regulatory T-Lymphocyte; Reporting; Research; Sampling; Secondary to; Sepsis; Survivors; TNF gene; Time; Training; cohort; cost; cytokine; cytokine release syndrome; emerging pathogen; fitness; gut microbiota; immune function; metabolomics; mortality; mouse model; novel; pathogen; pre-clinical; preclinical study; response; secondary infection; septic patients

Sepsis remains a major cause of death worldwide (11 million sepsis-related deaths were reported in 2017), and that costs associated with treating septic patients place a large burden on the healthcare industry. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Early stages of sepsis are marked by hyperinflammation driven by proinflammatory cytokines (i.e., IL-1β, IL-6, IFNγ, and TNF). Patients who survive the acute phase of sepsis display long-term impairments in immune function. This state of chronic immunoparalysis renders sepsis survivors increasingly susceptible to secondary infections. Consequently, there is a desperate need to better understand the cellular and molecular basis of acute sepsis pathophysiology and subsequent immune reprogramming that defines the prolonged immune suppression. CD4 T cells, essential for coordinating the cellular and humoral immune response to a range of pathogens under normal circumstances, are severely depleted during the acute stage of sepsis. The overall number of CD4 T cells gradually recover over time, but their functional capacity remains blunted for many months. For the past 10 years, we have focused our research to pursue the long-term goal of understanding how sepsis impacts the CD4 T cell compartment because of the key role played by CD4 T cells in the overall fitness of the immune system. We will continue our investigation of the cellular and molecular reprogramming of CD4 T cells during sepsis in three interconnected areas of future research: 1) Define the mechanism(s) by which regulatory CD4 T (Treg) cells expand during sepsis; 2) Perform an integrated discovery approach using genomics, proteomics, and metabolomics to elucidate the molecular basis of sepsis pathophysiology and CD4 T cell immunoparalysis; and 3) Determine how intestinal microbiota dysfunction during sepsis affects the magnitude of the cytokine storm and promotes CD4 T cell immunoparalysis and increased incidence of late-onset mortality. We will interrogate samples obtained from multiple cohorts of sepsis patients, as well as from preclinical mouse models of sepsis at the level of Ag-specific CD4 T cell populations. Our preclinical studies will be further strengthened by using a novel mouse model that mimics a critical aspect of human biology – exposure to multiple ongoing and resolved infections trains the immune system for robust responses to new pathogens – and will serve as an important and novel ‘transitional translational’ preclinical bridge between humans and SPF laboratory mice to mechanistically study CD4 T cell dysfunction and reprogramming during sepsis. Addressing these key gaps in knowledge regarding the effect of sepsis on CD4 T cell biology will likely reveal new points of intervention that can be exploited in the future to restore CD4 T cell-mediated immunity, and overall immune fitness, following sepsis.

败血症仍然是全球死亡的主要原因（2017年报道了1100万败血症相关的死亡）， 与治疗化粪池患者有关的成本对医疗保健行业造成了巨大的烧伤。败血症 是一种威胁生命的器官功能障碍，这是由于宿主对感染的失调反应引起的。早期阶段 败血症以促炎细胞因子（即IL-1β，IL-6，IFNγ和TNF）的过度炎症驱动为特征。 败血症急性期生存的患者在免疫功能中表现出长期损害。这种状态 慢性免疫分析使败血症存活越来越容易受到继发感染的影响。 因此，迫切需要更好地了解急性败血症的细胞和分子基础 病理生理学和随后的免疫重编程定义了长期的免疫抑制。 CD4 T细胞，对于对一系列病原体的细胞和体液免疫响应的协调至关重要 在正常情况下，在脓毒症的急性阶段严重耗尽。总数 CD4 T细胞随着时间的流逝逐渐恢复，但它们的功能能力仍然钝化了数月。为了 过去的十年，我们集中研究以追求理解败血症的长期目标 影响CD4 T细胞室，因为CD4 T细胞在整体适应性中扮演的关键作用 免疫系统。我们将继续研究CD4 T细胞的细胞和分子重编程 在未来研究的三个互连领域的败血症期间：1）定义调节性的机制 败血症期间CD4 T（Treg）细胞膨胀； 2）使用基因组学执行综合发现方法， 蛋白质组学和代谢组学阐明了脓毒症病理生理学和CD4 T细胞的分子基础 免疫分析； 3）确定脓毒症期间肠道菌群功能障碍如何影响大小 细胞因子风暴并促进CD4 T细胞免疫分析，并增加了晚期入射 死亡。我们将询问从多个败血症患者同类的样本以及 败血症的临床前小鼠模型在Ag特异性CD4 T细胞群体的水平上。我们的临床前研究 通过使用模仿人类生物学的关键方面的新型小鼠模型将进一步加强 暴露于多种正在进行的和解决的感染会训练免疫系统，以促进新的反应 病原体 - 并将成为重要而新颖的“过渡翻译”临床前桥 人类和SPF实验室小鼠在机械上研究CD4 T细胞功能障碍和重新编程 败血症。在有关败血症对CD4 T细胞生物学影响的知识中解决这些关键差距很可能 揭示新的干预点，将来可以探索以恢复CD4 T细胞介导的免疫力， 败血症后的总体免疫适应性。