T Regulatory cell responses in Toxoplasma-infected muscle

弓形虫感染肌肉中 T 调节细胞反应

• 批准号: 10556381
• 负责人: ELIZABETH WOHLFERT
• 金额: $ 45.8万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556381
• 关键词: Acute; Address; Affect; Amphiregulin; Autoimmunity; Brain; Cell physiology; Central Nervous System; Chronic; Chronically Ill; Cyst; Data; Epidermal Growth Factor Receptor; Equilibrium; FOXP3 gene; Genetic; Goals; Grant; Immune; Immune response; Impairment; Infection; Inflammation; Injury; Interferon Type II; Invaded; Macrophage; Mediating; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Parasites; Pathogenicity; Pathology; Patients; Play; Process; Production; Publishing; Quality of life; Recombinants; Regulatory T-Lymphocyte; Role; Skeletal Muscle; Supplementation; T cell response; T-Cell Development; Testing; Therapeutic Intervention; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; chronic infection; cytokine; immunopathology; immunoregulation; mortality; muscle form; muscle regeneration; pathogen; prevent; receptor; repaired; response; satellite cell; self-renewal; stem cells; tissue regeneration; tissue repair; transcription factor

After a tissue is infected, the invading pathogen must be controlled and the tissue must be repaired or else long-term morbidity and mortality will ensue. Toxoplasma gondii infections result in a non-resolving chronic infection with tissue cysts residing preferentially in skeletal muscle and the central nervous system. In contrast to the brain little is known about the immune response and immune-regulation in the infected muscle. Foxp3-expressing CD4+ regulatory T cells (Tregs) play a key role in controlling the immune response to infection and aid in tissue repair. Yet, we have found during chronic T. gondii infection muscle Tregs become pathogenic and cause inflammation instead of preventing it. We have shown these Tregs are Th1-polarized but do not produce IFNγ. Tregs in T. gondii-infected muscle produce low levels of amphiregulin, a cytokine critical in repairing immune-mediated pathology. We showed that Toxoplasma-induced immunopathology in muscle can be ameliorated by recombinant treatment with amphiregulin in chronically infected mice and returning function to the tissue. However it is unclear how amphiregulin mediates this effect. The overarching hypothesis for this proposal is that T-bet expression in skeletal muscle Tregs drives this pathogenic function by dampening production of key factors associated with normally suppressive Treg function. This hypothesis will be addressed in the following specific aims: (1) identify how T-bet drives the pathogenic function of Tregs in infected muscle and (2) define the role of amphiregulin in infected muscle during Toxoplasma infection. How a chronic infection alters the highly orchestrated immune-mediated regeneration of muscle is still poorly understood. Loss of muscle mass predicts reduced quality of life and often increased morbidity for chronically ill patients and so a better understanding of what drives this process is needed for directing therapeutic interventions.

组织被感染后，必须控制入侵的病原体并修复组织或 否则，将会出现长期的发病率和死亡率。弓形虫感染会导致 无法解决的慢性感染，组织囊肿优先存在于骨骼肌和 中枢神经系统。与大脑相比，我们对免疫反应知之甚少， 受感染肌肉的免疫调节。表达 Foxp3 的 CD4+ 调节性 T 细胞 (Treg) 发挥着 在控制对感染的免疫反应和帮助组织修复方面发挥着关键作用。然而，我们却发现 在慢性弓形虫感染期间，肌肉 Tregs 变得致病并引起炎症 来预防它。我们已经证明这些 Tregs 是 Th1 极化的，但不产生 IFNγ。 T 中的 Tregs。 弓形虫感染的肌肉产生低水平的双调蛋白，这是一种对修复至关重要的细胞因子 免疫介导的病理学。我们发现弓形虫引起的肌肉免疫病理学可以 通过对慢性感染小鼠和返回小鼠进行双调蛋白重组治疗可以改善 对组织的作用。然而，目前尚不清楚双调蛋白如何介导这种作用。首要的 该提议的假设是骨骼肌 Tregs 中的 T-bet 表达驱动了这种致病性 通过抑制与正常抑制性 Treg 功能相关的关键因子的产生来发挥功能。 这一假设将在以下具体目标中得到解决：（1）确定 T-bet 如何驱动 受感染肌肉中 Tregs 的致病功能，以及 (2) 定义双调蛋白在受感染肌肉中的作用 弓形虫感染期间的肌肉。慢性感染如何改变精心策划的 免疫介导的肌肉再生仍知之甚少。肌肉质量损失预测 慢性病患者的生活质量下降，发病率往往增加，因此更好的治疗方法 为了指导治疗干预，需要了解驱动这一过程的因素。