Abstract：
Zika virus (ZIKV) is an enveloped, single-stranded and positive-stranded RNA virus of the genus Flavivirus in the family Flaviviridae. ZIKV can cross the placental barrier and infect the fetus, causing microcephaly, congenital ZIKV syndrome, and even fetal death. ZIKV infection can also lead to testicular damage and male sterility. But no effective drugs and vaccines are available up to now. Previous studies have shown that the cathelicidin antimicrobial peptide LL-37 can protect against ZIKV infection. However, LL-37 is a secreted peptide, which can be easily degraded in vivo. We herein constructed exosome-loaded LL-37 (named LL-37-TM-exo and TM-LL-37-exo) using the transmembrane protein TM to load LL-37 onto the membrane of exosome. We found that exosome-loaded LL-37 could significantly inhibit ZIKV infection in vitro and in vivo, and LL-37-TM-exo had stronger antiviral activity than that of TM-LL-37-exo, which could significantly reduce ZIKV-induced testicular injury and sperm injury, and had broad-spectrum antiviral effect. Compared to free LL-37, exosome-loaded LL-37 showed a better serum stability, higher efficiency to cross the placental barrier, and stronger antiviral activity. The mechanism of exosome-loaded LL-37 against ZIKV infection was consistent with that of free LL-37, which could directly inactivate viral particles, reduce the susceptibility of host cells, and act on viral replication stage. Our study provides a novel strategy for the development of LL-37 against viral infection.
摘要：
寨卡病毒(ZIKV)是一种包膜病毒,单股,黄病毒科黄病毒属的正链RNA病毒。ZIKV可以穿过胎盘屏障并感染胎儿，导致小头畸形,先天性ZIKV综合征,甚至胎儿死亡.ZIKV感染也可导致睾丸损伤和男性不育。但目前还没有有效的药物和疫苗。先前的研究表明，凯萨林菌素抗菌肽LL-37可以预防ZIKV感染。然而,LL-37是一种分泌蛋白,很容易在体内降解。我们在本文中使用跨膜蛋白TM将LL-37负载到外泌体的膜上,构建了外泌体负载的LL-37(命名为LL-37-TM-exo和TM-LL-37-exo)。我们发现外泌体负载的LL-37可以在体外和体内显着抑制ZIKV感染，LL-37-TM-exo比TM-LL-37-exo具有更强的抗病毒活性，可显着减少ZIKV引起的睾丸损伤和精子损伤，并有广谱抗病毒作用。与游离LL-37相比，外泌体负载的LL-37显示出更好的血清稳定性，穿过胎盘屏障的效率更高，和更强的抗病毒活性。外泌体负载LL-37抗ZIKV感染的机制与游离LL-37可直接灭活病毒颗粒的机制一致，降低宿主细胞的易感性，并在病毒复制阶段发挥作用。我们的研究为开发针对病毒感染的LL-37提供了新的策略。
