Chowdhury Imran H, Lokugamage Nandadeva, Garg Nisha J
Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070, USA.
Institute for Human Infections and Immunity, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070, USA.
iScience. 2025 Jun 18;28(7):112926. doi: 10.1016/j.isci.2025.112926. eCollection 2025 Jul 18.
Poly(ADP-ribose) polymerase 1 (PARP1) inhibition improved the ventricular function in Chagas disease (CD). Here, we uncovered that depletion enhances cardiac health by regulating CD8T cell response against () infection. For this, and wild-type (WT) mice were challenged with and euthanized at acute and chronic phases of parasite replication and CD development, respectively. mice controlled the chronic parasite persistence and associated inflammatory pathology more effectively than WT mice. enhanced the maturation and stability of metabolically reprogrammed CD8 effector and memory T cells with increased cytotoxic effects against the parasite. Mechanistically, PARP1 depletion enhanced the NFATc1 translocation to Pdcd1 promoter in CD8T cells, altered the PD1:PDL1 stoichiometric ratio between CD8T and antigen-presenting cells, and promoted CD8T cell longevity and function during chronic infection. We conclude that molecular and chemical inhibitors of PARP1 would offer a potential therapy to arrest CD pathogenesis.
聚（ADP - 核糖）聚合酶1（PARP1）抑制改善了恰加斯病（CD）的心室功能。在此，我们发现基因敲除通过调节CD8 + T细胞针对（）感染的反应来增强心脏健康。为此，分别在寄生虫复制和CD发展的急性期和慢性期，用（）攻击基因敲除小鼠和野生型（WT）小鼠，并对其实施安乐死。基因敲除小鼠比WT小鼠更有效地控制了慢性寄生虫持续存在及相关的炎症病理。基因敲除增强了代谢重编程的CD8 +效应和记忆T细胞的成熟和稳定性，增强了对寄生虫的细胞毒性作用。从机制上讲，PARP1基因敲除增强了NFATc1向CD8 + T细胞中Pdcd1启动子的转位，改变了CD8 + T细胞与抗原呈递细胞之间的PD1：PDL1化学计量比，并在慢性（）感染期间促进了CD8 + T细胞的寿命和功能。我们得出结论，PARP1的分子和化学抑制剂将为阻止CD发病机制提供一种潜在的治疗方法。
