Polyphosphate and cardiac fibrosis by Trypanosoma cruzi

克氏锥虫的多磷酸盐与心脏纤维化

• 批准号: 10740934
• 负责人: ROBERTO DOCAMPO
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740934
• 关键词: Actins; Acute Myocarditis; Address; Adhesives; Affect; Americas; Binding; Blood Platelets; Cardiac; Cardiomyopathies; Cell membrane; Cell surface; Cells; Cessation of life; Chagas Disease; Chemotaxis; Chronic; Cicatrix; Clinical; Collagen; Deposition; Development; Elastin; Etiology; Extracellular Matrix; Failure; Fiber; Fibroblasts; Fibronectins; Fibrosis; Functional disorder; Generations; Glycosome; Heart Diseases; Heart Hypertrophy; Heart failure; Infection; Inflammation; Inflammatory; Laminin; Life Cycle Stages; Membrane Proteins; Molecular; Myofibroblast; Organ; Orthophosphate; Parasites; Pathogenesis; Pathogenicity; Pathology; Persons; Pharmacotherapy; Polymers; Polyphosphates; Polyps; Production; Proteins; Proteoglycan; Role; Signal Transduction; Signaling Molecule; Smooth Muscle; Stimulant; Stress Fibers; Structural Protein; Surface; Time; Tissues; Trypanocidal Agents; Trypanosoma cruzi; Vesicle; Work; cancer cell; chronic myocarditis; coronary fibrosis; experimental study; extracellular; extracellular vesicles; flexibility; interstitial; mast cell; neutrophil; posaconazole; prevent; response to injury; side effect; vaccine access

Abstract Cardiomyopathy is the most frequent clinical manifestation of Chagas disease. The pathogenesis of the heart disease is attributed to the persistence of T. cruzi leading to chronic inflammation, fibrosis, cardiac hypertrophy and heart failure. Fibrosis results from excessive accumulation of extracellular matrix (ECM) by terminally differentiated fibroblast (myofibroblasts) in response to injury or illness and leads to organ disfunction and failure. Interstitial fibrosis occurs in both acute and chronic myocarditis caused by T. cruzi, and is characterized by the deposition of ECM components. The parasite per se appears to be responsible since deposition of ECM components (fibronectin, laminin, and collagen) also occurs in cultures of cardiac myofibroblasts infected by the parasite, where no inflammatory cells are present, and is reversible upon treatment with the trypanocidal agent posaconazole. Recent work has discovered that polyphosphate (polyP), acting as a cell signaling molecule, is a potent inducer of fibroblast chemotaxis, myofibroblast differentiation, and production of ECM components, such as a-smooth muscle actin, stress fibers, and collagen. We have found that polyP is released by cells such as platelets, and mast cells. PolyP is abundantly present in all life cycle stages of T. cruzi, reaching cellular mM concentrations, and is located in acidocalcisomes, glycosomes, nucleoli, and in the outer surface of the parasite. It is not known whether polyP is also released from T. cruzi although the parasite is able to release extracellular vesicles budding from the plasma membrane, and the localization of polyP in the outer surface of the parasite suggest that it is. In summary, there is evidence that: (1) T. cruzi per se stimulates fibroblast to myofibroblast transition and deposition of ECM components; (2) deposition of ECM components by T. cruzi-infected cardiac myofibroblasts occurs in the absence of inflammatory cells, (3) polyP is involved in fibroblast chemotaxis, myofibroblast differentiation, and production of ECM components; and (4) polyP is abundant in T. cruzi and expressed in the outer surface of the cells and is released in extracellular vesicles (EVs). We will explore two hypotheses that are related to our recent findings: 1. That T. cruzi surface or released polyP stimulates fibrosis; and 2. That T. cruzi surface or released polyP is involved in the deposition of ECM components by myofibroblasts through the activation of signaling cascades.

摘要 心肌病是南美锥虫病最常见的临床表现。的发病机制 心脏病是由于T. cruzi导致慢性炎症、纤维化、心脏 肥大和心力衰竭。纤维化是由于细胞外基质（ECM）的过度积累 终末分化的成纤维细胞（肌成纤维细胞）对损伤或疾病的反应，并导致器官 功能障碍和失败。间质纤维化发生在由T.克鲁兹， 并且其特征在于ECM组分的沉积。寄生虫本身似乎是 由于ECM成分（纤连蛋白、层粘连蛋白和胶原蛋白）的沉积也发生在心肌细胞的培养物中， 肌成纤维细胞被寄生虫感染，其中不存在炎性细胞，并且在 用杀锥虫剂泊沙康唑治疗。最近的研究发现， 作为细胞信号传导分子，聚P（polyP）是成纤维细胞趋化性、肌成纤维细胞趋化性和成纤维细胞趋化性的有效诱导剂。 分化和ECM组分的产生，如α-平滑肌肌动蛋白、应力纤维和 胶原我们已经发现polyP由诸如血小板和肥大细胞的细胞释放。息肉 大量存在于T. cruzi，达到细胞mM浓度，并位于 酸钙体、糖体、核仁和寄生虫的外表面。目前还不知道是否 polyP也从T. cruzi虽然寄生虫能够释放细胞外囊泡出芽 从质膜，和本地化的polyP在外表面的寄生虫表明，它 是.综上所述，有证据表明：（1）T. cruzi本身刺激成纤维细胞向肌成纤维细胞转变 （2）T.克氏病毒感染的心脏 肌成纤维细胞在不存在炎性细胞的情况下发生，（3）聚P参与成纤维细胞趋化性， 肌成纤维细胞分化和ECM成分的产生;和（4）聚P在T.克鲁兹和 在细胞的外表面表达并在细胞外囊泡（EV）中释放。我们将探讨 与我们最近的发现相关的两个假设：1。那个T cruzi表面或释放的polyP刺激 纤维化;和2.那个T cruzi表面或释放的polyP参与ECM组分的沉积， 通过信号级联的激活促进肌成纤维细胞的增殖。