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.

脓毒症仍然是全球死亡的主要原因（2017 年报告了 1100 万人因脓毒症相关死亡）， 治疗脓毒症患者的相关费用给医疗保健行业带来了巨大的负担。 是由宿主对感染的早期反应失调引起的危及生命的器官功能障碍。 脓毒症的特点是促炎细胞因子（即 IL-1β、IL-6、IFNγ 和 TNF）驱动的过度炎症。 在脓毒症急性期幸存的患者表现出免疫功能的长期损害。 慢性免疫麻痹使脓毒症幸存者越来越容易受到继发感染。 经过测试，迫切需要更好地了解急性脓毒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，对于协调对一系列病原体的细胞和体液免疫反应至关重要 正常情况下，脓毒症急性期的总数严重减少。 随着时间的推移，CD4 T 细胞逐渐恢复，但其功能在数月内仍处于减弱状态。 过去 10 年，我们的研究重点是追求了解脓毒症如何发生的长期目标 影响 CD4 T 细胞区室，因为 CD4 T 细胞在 CD4 T 细胞的整体健康中发挥着关键作用 我们将继续研究 CD4 T 细胞的细胞和分子重编程。 在脓毒症期间，未来研究的三个相互关联的领域：1）定义监管机制 CD4 T (Treg) 细胞在脓毒症期间扩增；2) 使用基因组学进行综合发现方法， 蛋白质组学和代谢组学阐明脓毒症病理生理学和 CD4 T 细胞的分子基础 3) 确定败血症期间肠道微生物群功能障碍如何影响严重程度 细胞因子风暴并促进 CD4 T 细胞免疫麻痹并增加迟发型发病率 我们将询问从多个脓毒症患者队列以及从脓毒症患者中获得的样本。 Ag 特异性 CD4 T 细胞群水平的临床前小鼠脓毒症模型。 将通过使用模仿人类生物学关键方面的新型小鼠模型来进一步加强 - 接触多种正在发生和已解决的感染可以训练免疫系统对新的感染做出强有力的反应 病原体——并将作为一个重要且新颖的“过渡性转化”临床前桥梁 人类和 SPF 实验小鼠机械地研究 CD4 T 细胞功能障碍和重编程 解决脓毒症对 CD4 T 细胞生物学影响的这些关键知识空白可能会。 揭示未来可用于恢复 CD4 T 细胞介导的免疫的新干预点， 以及脓毒症后的整体免疫健康。