Immunoregulation of cellular immunity and tissue homeostasis during Chagas' disease

恰加斯病期间细胞免疫和组织稳态的免疫调节

• 批准号: 10600054
• 负责人: Eva V Acosta Rodriguez
• 金额: $ 13.38万
• 依托单位: NATIONAL RESEARCH COUNCIL OF ARGENTINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600054
• 关键词: Acute; Affect; Animal Model; Area; CD8-Positive T-Lymphocytes; Cardiac; Cells; Cellular Immunity; Chagas Disease; Chronic; Chronic Phase; Clinical; Country; Data; Development; Disease; Disease Progression; Economic Burden; Elements; Equilibrium; Evaluation; FOXP3 gene; Flow Cytometry; Generations; Genetic Transcription; Goals; Health; Heterogeneity; Homeostasis; Host resistance; Human; Immune response; Immunity; Immunologics; Infection; Knowledge; Latin America; Link; Location; Lymphoid; Mediating; Mediator; Metabolic; Methodology; Molecular; Mus; Outcome; Parasite Control; Parasites; Parasitic Diseases; Parasitic infection; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Persons; Phase; Phenotype; Play; Population; Property; Publishing; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Research; Role; Sampling; Severities; Severity of illness; T cell response; Testing; Tissue Preservation; Tissues; Translating; Trypanosoma cruzi; Vaccination; acute infection; chronic infection; design; immunopathology; immunoregulation; insight; metabolic fitness; microbial; mortality; novel; novel therapeutics; pathogen; physically handicapped; prevent; programs; rational design; residence; response; social; therapy design; tissue repair; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America but cases are increasing in non-endemic countries, becoming a global concern. It affects 6 million people and imposes a major economic burden due to early mortality and physical disabilities. Disease progression, from symptomless to severe, is linked to parasite heterogeneity and a variable host immune response. Development of robust CD8+ T cell immunity is a key element of host resistance and T. cruzi persistence and chronic Chagas disease has been associated to suboptimal CD8+ T cell responses. Despite this, the knowledge about pathways that promote robust protective CD8+ T cell immunity to T. cruzi remains incomplete and for instance, the metabolic hurdles faced by effector CD8+ T cells for expansion and differentiation have been barely explored. Also, the progression of T. cruzi infection is thought to be significantly modulated by regulatory immune responses that limit parasite-specific immunity as well as infection-associated immunopathology by mechanisms poorly understood. In this context, defining how effector and regulatory pathways intertwined to allow the generation of optimal cellular immunity against T. cruzi preserving of tissue homeostasis is crucial to understand Chagas disease pathogenesis. In this direction, our published data showed that Treg cells became activated during T. cruzi infection and acquired phenotypic attributes that markedly changed along the infection. Thus, Treg cells acquired features linked to the regulation of type 1 responses and limited CD8+ T cell immunity during the infection acute phase, likely delaying parasite control and favoring chronicity. In contrast, preliminary data demonstrate that Treg cells with tissue repair ties, which were disfavored during the acute phase, accumulated during the chronic phase in nonlymphoid tissues considered targets of T. cruzi and reduced tissue damage. Altogether, our findings highlight numerous changes in the phenotypic and functional profile as well as main location of specialized Treg cells in the transition from acute to chronic phase, suggesting that Treg cell roles switch from deleterious to protective in the course of this infection. A comprehensive characterization of phenotype, function and transcriptional program of Treg cells in different tissues, together with the manipulation of this regulatory subset by different strategies will allow us to define the mechanisms underlying Treg cell mediated regulation of effector immunity and immunopathology in acute and chronic experimental T. cruzi infection. These approaches will guide our evaluation of effector and regulatory pathways and their association to the clinical severity in samples of patients with chronic Chagas disease in order to translate our finding to human health. Altogether, our studies will provide meaningful data about different interacting pathways and, possibly, new mediators that participate in the regulation of effector cellular immunity to T. cruzi and the development of chronic pathology. This information will identify potential new targets for the rational design of therapies for Chagas´ disease and, likely, other chronic infections.

项目摘要/摘要 由原生动物锥虫瘤引起的Chagas病在拉丁美洲是内在的，但病例是 在非目标国家中增加，成为全球关注的问题。它影响了600万人，并强加了 由于早期死亡和身体残疾而导致的重大经济负担。疾病进展，无症状 与寄生虫异质性和可变宿主免疫反应有关。健壮的发展 CD8+ T细胞免疫是宿主抗性和T. cruzi持久性和慢性查加斯病的关键要素 与次优的CD8+ T细胞反应有关。尽管如此，关于途径的知识 促进对Cruzi T. Cruzi的强大保护CD8+ T细胞免疫保持不完整，例如代谢 效应子CD8+ T细胞面临的障碍几乎没有探索。另外， 据认为，克鲁兹感染的进展被认为是通过调节性免疫反应显着调节的 通过机制限制寄生虫特异性免疫以及与感染相关的免疫病理学 理解。在这种情况下，定义效应器和监管途径如何交织以使生成 对抗组织体内稳态的最佳细胞免疫力对于理解Chagas至关重要 疾病发病机理。在这个方向上，我们发布的数据表明，Treg细胞在T期间被激活。 克鲁兹感染和获得的表型属性，这些属性沿感染发生了明显变化。那，Treg细胞 与1型响应调节和有限的CD8+ T细胞免疫相关的获得的功能 感染急性期，可能延迟寄生虫控制并有利于慢性。相反，初步数据 证明在急性期不受组织的treg细胞累积 在非淋巴组织中的慢性期间，认为克鲁齐的靶标和减少组织损伤。 总之，我们的发现突出了表型和功能概况以及主要的许多变化 专门的Treg细胞在从急性到慢性相的过渡中的位置，表明Treg细胞的作用 在此感染过程中，从有害的切换到保护。全面的特征 Treg细胞在不同组织中的表型，功能和转录程序以及 通过不同策略操纵这种监管子集将使我们能够定义基本机制 Treg细胞介导的急性和慢性实验T中的效应子免疫病理学和免疫病理学的调节。 克鲁兹感染。这些方法将指导我们对效应器和监管途径及其的评估 与慢性查加斯病患者样本的临床严重程度有关，以翻译我们 寻找人类健康。总之，我们的研究将提供有关不同互动的有意义的数据 参与效应子细胞免疫的途径以及可能的新介质 以及慢性病理学的发展。该信息将确定理性的潜在新目标 设计芝加哥疾病以及其他慢性感染的疗法。