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: 10441993
• 负责人: ELIZABETH WOHLFERT
• 金额: $ 46.76万
• 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/10441993
• 关键词: Acute; Address; Affect; Amphiregulin; Autoimmunity; Brain; Chronic; Chronically Ill; Cyst; Data; Development; Epidermal Growth Factor Receptor; Equilibrium; FOXP3 gene; Genetic; Goals; Grant; Immune; Immune response; Impairment; Infection; Inflammation; Injury; Interferon Type II; Invaded; Mediating; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Neuraxis; Parasites; Pathogenicity; Pathology; Patients; Play; Process; Production; Publishing; Quality of life; Recombinants; Regulatory T-Lymphocyte; Role; Skeletal Muscle; Supplementation; Testing; Therapeutic Intervention; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; chronic infection; cytokine; immunopathology; immunoregulation; macrophage; mortality; muscle form; muscle regeneration; pathogen; prevent; receptor; regeneration function; 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.

在组织被感染后，必须控制入侵的病原体，并且必须修复组织， 否则，长期的发病率和死亡率将随之而来。弓形虫感染导致 未消退的慢性感染，组织囊肿优先位于骨骼肌， 中枢神经系统与大脑相反，人们对免疫反应知之甚少， 感染肌肉中的免疫调节。表达Foxp3的CD4+调节性T细胞（TCR4）在免疫应答中发挥重要作用。 在控制对感染的免疫反应和帮助组织修复中起关键作用。然而，我们发现 慢性T.弓形虫感染肌肉TIPs成为致病性，并引起炎症， 我们已经证明这些T细胞是Th1极化的，但不产生IFN γ。特林河 感染弓形虫的肌肉产生低水平的双调蛋白，一种在修复中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 通过用双调蛋白重组治疗慢性感染的小鼠， 对组织的作用。然而，尚不清楚双调蛋白如何介导这种效应。总体 这一建议假设是骨骼肌中的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 双调蛋白在感染肌肉中的致病功能和（2）确定双调蛋白在感染肌肉中的作用 弓形虫感染时的肌肉慢性感染如何改变高度协调的 免疫介导肌肉再生仍然知之甚少。肌肉质量的损失预示着 生活质量下降，慢性病患者的发病率往往增加，因此， 需要了解是什么驱动了这一过程，以指导治疗干预。