Endogenous cathelicidin is required for protection against ZIKV-caused testis damage via inactivating virons
Endogenous cathelicidin is required for protection against ZIKV-caused testis damage via inactivating virons
复制标题
需要内源性导管素通过灭活病毒来防止 ZIKV 引起的睾丸损伤
DOI：
10.1016/j.antiviral.2022.105248
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发表时间：
2022-01-19
影响因子：
7.6
通讯作者：
Wei, Lin
中科院分区：
文献类型：
--
作者：
Liu, Zhen;Wu, Jing;Wei, Lin
已显示Cathelicidins在体外有效抑制黄病毒复制。然而，小鼠和人类内源性cathelicidins对体内黄病毒感染的影响很少有人知道。我们在本文中发现，小鼠内源性凯萨林菌素CRAMP在寨卡病毒（ZIKV）感染后显著上调。CRAMP缺乏显著地加剧了ZIKV在睾丸中的复制，并且加重了小鼠中ZIKV诱导的睾丸损伤和精子损伤，表明需要内源性凯萨林菌素来保护小鼠免受ZIKV引起的雄性不育。体外抗病毒试验表明，小鼠cathelidin CRAMP和人cathelicidin LL-37均明显降低ZIKV引起的细胞病变效应，并抑制ZIKV在Vero细胞中的复制。抗病毒机制表明，它们都通过与ZIKV病毒结合并诱导ZIKV基因组RNA泄漏来直接灭活ZIKV病毒，从而灭活ZIKV病毒。体内抗病毒测定表明，当CRAMP或LL-37与ZIKV的静脉内注射平行或在静脉内注射后1小时静脉内注射时，它们两者都有效地抑制C57 BL/6 J和IFN α/β受体缺陷（Ifnar 1（-/-））小鼠中的ZIKV复制，这意味着CRAMP和LL-37有效地灭活ZIKV颗粒，并表现出针对体内ZIKV感染的治疗潜力。我们的发现揭示了内源性凯萨林菌素CRAMP和LL 37作为ZIKV的灭活剂，并有效地防止ZIKV复制和ZIKV诱导的男性不育，突出了它们用于治疗ZIKV感染的潜力。
Cathelicidins have been shown to effectively inhibit flavivirus replication in vitro. However, the effects of mouse and human endogenous cathelicidins on flavivirus infection in vivo are rarely known. We herein found that mouse endogenous cathelicidin CRAMP was significantly up-regulated upon Zika virus (ZIKV) infection. CRAMP deficiency markedly exacerbated ZIKV replication in testis, and aggravated ZIKV-induced testicular damage and spermatic damage in mice, indicating that endogenous cathelicidin is required for protection against ZIKVcaused male infertility in mice. In vitro antiviral assay showed that both mouse cathelidin CRAMP and human cathelicidin LL-37 obviously reduced ZIKV-caused cytopathic effect and inhibited ZIKV replication in Vero cells. Antiviral mechanism revealed that they both directly inactivated ZIKV virons by binding to ZIKV virons and inducing the leakage of ZIKV genomic RNA, consequently inactivated ZIKV virons. In vivo antiviral assay indicated that both of them effectively inhibited ZIKV replication in C57BL/6J and IFN alpha/beta receptor-deficient (Ifnar1(-/-)) mice when CRAMP or LL-37 was intravenously injected in parallel with or at 1 h after intravenous injection of ZIKV, implying that CRAMP and LL-37 effectively inactivated ZIKV particles and exhibited therapeutic potential against ZIKV infection in vivo. Our findings reveal that endogenous cathelicidin CRAMP and LL37 act as inactivators of ZIKV, and effectively protect against ZIKV replication and ZIKV-induced male infertility, highlighting their potential for therapy of ZIKV infection.