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: 10400169
• 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/10400169
• 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; Interferon Type II; Interleukin-1 beta; Interleukin-6; Intervention; Investigation; Knowledge; Laboratory mice; Life; Modeling; Molecular; Mus; Nosocomial Infections; Organ; Patients; Phase; Play; Population; 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.

脓毒症仍然是全世界的主要死亡原因(2017年报告了1100万例与败血症有关的死亡)， 与治疗败血症患者相关的成本给医疗行业带来了巨大的负担。脓毒症 是一种威胁生命的器官功能障碍，由宿主对感染的失调反应引起。早期阶段 脓毒症的特征是由促炎细胞因子(即IL-1β、IL-6、干扰素γ和肿瘤坏死因子)驱动的炎症反应。 在脓毒症急性期幸存下来的患者表现出长期的免疫功能损害。这种状态 慢性免疫麻痹使败血症幸存者越来越容易受到继发感染。 因此，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新编程，定义了长期的免疫抑制。 CD4T细胞，对协调对一系列病原体的细胞和体液免疫反应至关重要 在正常情况下，在脓毒症的急性期严重耗尽。总人数 随着时间的推移，CD4T细胞逐渐恢复，但其功能能力在数月内仍然迟钝。对于 在过去的10年里，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CD4T细胞隔间，因为CD4T细胞在机体整体健康状况中起着关键作用 免疫系统。我们将继续研究CD4T细胞的细胞和分子重编程 脓毒症期间三个相互关联的领域的未来研究：1)确定机制(S)，通过 CD4T(Treg)细胞在脓毒症期间扩张；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CD4T细胞的分子基础 免疫麻痹；以及3)确定脓毒症期间肠道微生物区系功能障碍如何影响程度 细胞因子风暴和促进CD4T细胞免疫麻痹和增加晚发性发病率 死亡率。我们将询问从多个败血症患者队列中获得的样本，以及从 在抗原特异性CD4T细胞水平上的临床前脓毒症小鼠模型。我们的临床前研究 通过使用一种新的小鼠模型来模拟人类生物学的一个关键方面，将进一步加强- 暴露在多种持续和已解决的感染中，训练免疫系统对新的 病原体--并将成为一座重要而新颖的临床前过渡桥梁 人类和SPF实验室小鼠机械研究CD4T细胞功能障碍和重新编程 败血症。解决关于脓毒症对CD4T细胞生物学影响的知识中的这些关键差距可能会 揭示了未来可用于恢复CD4T细胞介导的免疫的新的干预点， 以及败血症后的整体免疫状况。