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 由原生动物克氏锥虫引起的恰加斯病在拉丁美洲是地方病，但有病例 在非流行国家增加，成为全球关注的问题。它影响了600万人，并强加了 由于过早死亡和身体残疾造成的重大经济负担。疾病进展，从无症状 严重时，与寄生虫的异质性和可变的宿主免疫反应有关。健壮的发展 CD8+T细胞免疫是宿主抵抗和弓形虫持续存在与慢性恰加斯病的关键因素 与不理想的CD8+T细胞反应有关。尽管如此，关于路径的知识 促进CD8+T细胞对弓形虫的强大保护性免疫仍然不完整，例如，代谢 效应者CD8+T细胞在扩增和分化过程中所面临的障碍几乎没有被探索过。另外， 克氏毛滴虫感染的进展被认为是由调节性免疫反应显著调节的， 限制寄生虫特异性免疫以及感染相关免疫病理学的机制很差 明白了。在此背景下，定义效应器和调节通路如何相互交织以允许生成 对克氏毛滴虫的最佳细胞免疫保护组织动态平衡是理解查加斯的关键 疾病发病机制。在这个方向上，我们发表的数据显示，Treg细胞在T。 CRUZI感染和后天获得的表型属性在感染过程中发生了显著变化。因此，Treg细胞 获得性特征与调节1型反应和有限的CD8+T细胞免疫有关 感染急性期，可能延缓寄生虫控制，有利于慢性化。相比之下，初步数据 证明具有组织修复联系的Treg细胞，在急性期不受欢迎，积累起来 在慢性期，非淋巴组织被认为是克氏支原体的靶标，减少了组织损伤。 总之，我们的发现突出了表型和功能图谱以及主要的 特化Treg细胞在从急性期向慢性期转变过程中的定位，提示Treg细胞在其中的作用 在这种感染过程中从有害转变为保护性。对…的全面描述 不同组织中Treg细胞的表型、功能和转录程序，以及 通过不同的策略操纵这一监管子集将使我们能够定义潜在的机制 Treg细胞对急性和慢性实验性T细胞效应免疫和免疫病理的调节作用 克鲁兹病毒感染。这些方法将指导我们对效应器和调控途径以及它们的 慢性恰加斯病患者样本与临床严重程度的关系 对人类健康的影响。总之，我们的研究将提供关于不同相互作用的有意义的数据 参与调节克氏毛滴虫效应器细胞免疫的途径和可能的新介质 以及慢性病理学的发展。这些信息将确定Rational的潜在新目标 针对恰加斯病和可能的其他慢性感染的治疗方法的设计。