Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
ACS Infect Dis. 2021 Mar 12;7(3):566-578. doi: 10.1021/acsinfecdis.0c00590. Epub 2021 Feb 11.
Chagas cardiomyopathy is the consequence of a compromised electrical and mechanical cardiac function, with parasite persistence, unbalanced inflammation, and pathological tissue remodelling, being intricately related to myocardial aggression and impaired function. Recent studies have shown that Wnt signaling pathways play a critical role in the pathogenesis of cardiac and vascular diseases. In addition, we have reported that infection activates Wnt signaling to promote intracellular replication of the parasites in macrophages, with the treatment of mice with IWP-L6 (an inhibitor of the -acyl-transferase, PORCN, responsible for the post-translational modifications necessary for Wnt protein secretion) being able to diminish parasitemia and tissue parasitism. Here, we show that inhibition of Wnt signaling during the acute phase of infection controls the parasite replication, inhibits the development of parasite-prone and fibrosis-prone Th2-type immune response, and prevents the development of cardiac abnormalities characteristics of chronic Chagas disease. Our results suggest that the Wnt signaling pathway might be a potential target to prevent the development of -induced cardiomyopathy.
克氏锥虫相关性心肌病是电-机械心脏功能受损的结果，寄生虫持续存在、炎症失衡以及病理性组织重构与心肌侵袭和功能障碍密切相关。最近的研究表明，Wnt 信号通路在心脏和血管疾病的发病机制中起着关键作用。此外，我们还报告称，感染激活 Wnt 信号通路，促进巨噬细胞内寄生虫的复制，用 IWP-L6（-酰基转移酶 PORCN 的抑制剂，负责 Wnt 蛋白分泌所必需的翻译后修饰）治疗感染小鼠能够降低寄生虫血症和组织寄生虫病。在这里，我们表明，在感染的急性期抑制 Wnt 信号通路可以控制寄生虫的复制，抑制易发生寄生虫和纤维化的 Th2 型免疫反应的发展，并防止慢性克氏锥虫病特征性的心脏异常的发展。我们的研究结果表明，Wnt 信号通路可能是预防克氏锥虫感染引起的心肌病的潜在靶点。
