抗菌肽cathelicidins具广谱抗包膜病毒功能，但其对非包膜病毒的功能尚不明确。在非包膜病毒CVB3感染早期，我们发现cathelicidin在小鼠心脏上调最为显著，并以间接的方式显著抑制了CVB3复制；CVB3感染可诱导心肌细胞和小鼠上调分泌外泌体，且该外泌体可感染心肌细胞，人或鼠源cathelicidin可抑制其上调和感染。我们推测cathelicidins可通过抑制外泌体介导的病毒感染而发挥抗病毒作用。为证实该推测，我们拟以cathelicidin敲除小鼠确证其抑制CVB3感染的功能；在心肌细胞和小鼠中，阐明其是否通过两亲性螺旋结构与外泌体脂质外膜结合并致其穿孔，从而抑制外泌体介导的病毒传播、免疫逃避和机体免疫损伤；探索其是否调控病毒感染中的细胞自噬、凋亡、ERK激酶和宿主抗病毒应答。本课题将提供抗菌肽cathelicidins抵抗非包膜病毒的新机制和病毒性心肌炎防治的新策略。

Cathelicidin antimicrobial peptides are a family of gene-encoded peptide effectors of innate immunity for antimicrobial defense and, more recently, immunomodulation. Cathelicidins show broad-spectrum antiviral activity against enveloped virus. However, the role and mechanism of cathelicidins against nonenveloped virus infection remain elusive. Preliminary results showed that the expression of cathelicidin (CRAMP) was the most significantly up-regulated in the heart of CVB3-induced VMC mice. And CVB3 replication in heart and viral myocarditis were significantly inhibited by intraperitoneal injection of cathelicidins. Furthermore, cathelicidins inhibited the replication of CVB3 in a direct manner. In addition, we found that CVB3 infection significantly induced the up-regulation of exosome secretions in cardiomyocytes and mice, and the purified exosomes could infect cardiomyocytes. But cathelicidins could inhibit the up-regulated secretion of exosome in cardiomyocytes and mice and their infection in cardiomyocytes. On the basis of these results, we hypothesize that cathelicidins can bind to the envelope membrane of exosomes through amphipathic structure and inhibit exosome-mediated CVB3 infection. Next, we will use CRAMP-deficient mice to further confirm the antiviral and immunoregulatory effects of cathelicidins against nonenveloped CVB3 replication and CVB3 infection induced VMC. Besides, we will explore the relative mechanisms in cardiomyocytes and VMC mice. We will investigate the effects of cathelicidins on exosome-mediated virus transmission, immune escape and immune injury. And we will explore other possible mechanisms, including the activation of CVB3 replication-dependent autophagy, apotosis and ERK, as well as the antiviral responses of type I IFNs/CD8+ T cells. Hopefully, we will propose an innovative understanding for the role of cathelicidins against nonenveloped virus infection, and provide cathelicidin antimicrobial peptides as novel therapeutic targets for VMC therapy.