The First Affiliated Hospital of Nanchang University and School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China.
The Second Clinical Medical College, Nanchang University, Nanchang, China.
J Virol. 2024 Sep 17;98(9):e0080524. doi: 10.1128/jvi.00805-24. Epub 2024 Aug 28.
Coxsackievirus group B3 (CVB3) belongs to the genus of the family and is the main pathogen underlying viral myocarditis (VMC). No specific therapeutic is available for this condition. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle that converts citrulline and aspartic acid to argininosuccinate. Here, we found that CVB3 and its capsid protein VP2 inhibit the autophagic degradation of ASS1 and that CVB3 consumes citrulline to upregulate ASS1, triggers urea cycle metabolic reprogramming, and then activates macrophages to develop pro-inflammatory polarization, thereby promoting the occurrence and development of VMC. Conversely, citrulline supplementation to prevent depletion can downregulate ASS1, rescue macrophage polarization, and alleviate the pathogenicity of VMC. These findings provide a new perspective on the occurrence and development of VMC, revealing ASS1 as a potential new target for treating this disease.
Viral myocarditis (VMC) is a common and potentially life-threatening myocardial inflammatory disease, most commonly caused by CVB3 infection. So far, the pathogenesis of VMC caused by CVB3 is mainly focused on two aspects: one is the direct myocardial injury caused by a large number of viral replication in the early stage of infection, and the other is the local immune cell infiltration and inflammatory damage of the myocardium in the adaptive immune response stage. There are few studies on the early innate immunity of CVB3 infection in myocardial tissue, but the appearance of macrophages in the early stage of CVB3 infection suggests that they can play a regulatory role as early innate immune response cells in myocardial tissue. Here, we discovered a possible new mechanism of VMC caused by CVB3, revealed new drug targets for anti-CVB3, and discovered the therapeutic potential of citrulline for VMC.
柯萨奇病毒 B3（CVB3）属于 科的 属，是病毒性心肌炎（VMC）的主要病原体。目前尚无针对这种疾病的特定治疗方法。精氨琥珀酸合成酶 1（ASS1）是尿素循环中的关键酶，可将瓜氨酸和天冬氨酸转化为精氨琥珀酸。在这里，我们发现 CVB3 及其衣壳蛋白 VP2 抑制 ASS1 的自噬降解，CVB3 消耗瓜氨酸上调 ASS1，触发尿素循环代谢重编程，然后激活巨噬细胞产生促炎极化，从而促进 VMC 的发生和发展。相反，补充瓜氨酸以防止耗尽可以下调 ASS1，挽救巨噬细胞极化，并减轻 VMC 的致病性。这些发现为 VMC 的发生和发展提供了新的视角，揭示了 ASS1 作为治疗这种疾病的潜在新靶点。
病毒性心肌炎（VMC）是一种常见且潜在危及生命的心肌炎症性疾病，最常见于 CVB3 感染。到目前为止，CVB3 引起的 VMC 的发病机制主要集中在两个方面：一是感染早期大量病毒复制引起的直接心肌损伤，二是适应性免疫反应阶段局部免疫细胞浸润和心肌炎症损伤。关于 CVB3 感染心肌组织的早期先天免疫研究较少，但 CVB3 感染早期巨噬细胞的出现表明它们可以作为心肌组织中早期先天免疫反应细胞发挥调节作用。在这里，我们发现了 CVB3 引起的 VMC 的一种可能的新机制，揭示了抗 CVB3 的新药物靶点，并发现了瓜氨酸治疗 VMC 的潜力。
