A cathelicidin antimicrobial peptide from Hydrophis cyanocinctus inhibits Zika virus infection by downregulating expression of a viral entry factor.
A cathelicidin antimicrobial peptide from Hydrophis cyanocinctus inhibits Zika virus infection by downregulating expression of a viral entry factor.
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来自 Hydrophisyanocinctus 的抗菌肽通过下调病毒进入因子的表达来抑制寨卡病毒感染
DOI：
10.1016/j.jbc.2022.102471
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发表时间：
2022-10
影响因子：
4.8
通讯作者：
Wei, Lin
中科院分区：
文献类型：
--
作者：
Wang, Jing;Jiang, Bingyan;Wang, Kezhen;Dai, Jianfeng;Dong, Chunsheng;Wang, Yipeng;Zhang, Peng;Li, Min;Xu, Wei;Wei, Lin
寨卡病毒(ZIKV)是一种重新出现的黄病毒，会导致小头畸形和睾丸损伤等疾病。寨卡病毒的传播已经成为一个主要的公共卫生问题。最近的研究表明，抗菌肽是筛选具有广谱抗病毒活性的候选抗病毒药物的理想来源，包括对ZIKV的抗病毒活性。在此，我们发现HC-Cath是我们先前工作中从海蛇海蛇中鉴定的一种盲肠毒素抗菌肽，对宿主细胞中的ZIKV感染具有保护作用，并在C57BL/6J小鼠、Ifnar1−/−小鼠和妊娠小鼠中显示了预防和治疗效果。有趣的是，我们发现HC-Cath通过下调介导ZIKV感染的家族激酶受体Ax1的表达来降低宿主细胞对ZIKV的敏感性，并随后逆转了Axl对宿主I型干扰素反应的负调控。此外，我们还发现环氧合酶-2/前列腺素E_2/腺苷环化酶/蛋白激酶A途径参与了HC-Cath介导的Ax1下调，HC-Cath还通过破坏病毒膜直接灭活了ZIKV颗粒。最后，虽然我们发现HC-Cath在ZIKV感染的后期并不起作用，但结构-功能关系研究表明，α-螺旋和苯丙氨酸残基是其保护最初感染ZIKV效果的关键结构要求。综上所述，我们证明了HC-Cath通过下调Ax1的表达以及灭活病毒粒子来预防和治疗ZIKV感染。我们的发现揭示了放线菌素抗病毒感染的新机制，并突出了HC-Cath在预防和治疗寨卡病毒感染方面的潜力。
Zika virus (ZIKV) is a re-emerging flavivirus that causes conditions such as microcephaly and testis damage. The spread of ZIKV has become a major public health concern. Recent studies indicated that antimicrobial peptides are an ideal source for screening antiviral candidates with broad-spectrum antiviral activities, including against ZIKV. We herein found that Hc-CATH, a cathelicidin antimicrobial peptide identified from the sea snake Hydrophis cyanocinctus in our previous work, conferred protection against ZIKV infection in host cells and showed preventative efficacy and therapeutic efficacy in C57BL/6J mice, Ifnar1−/− mice, and pregnant mice. Intriguingly, we revealed that Hc-CATH decreased the susceptibility of host cells to ZIKV by downregulating expression of AXL, a TAM (TYRO3, AXL and MERTK) family kinase receptor that mediates ZIKV infection, and subsequently reversed the negative regulation of AXL on host’s type I interferon response. Furthermore, we showed that the cyclo-oxygenase-2/prostaglandin E2/adenylyl cyclase/protein kinase A pathway was involved in Hc-CATH-mediated AXL downregulation, and Hc-CATH in addition directly inactivated ZIKV particles by disrupting viral membrane. Finally, while we found Hc-CATH did not act on the late stage of ZIKV infection, structure–function relationship studies revealed that α-helix and phenylalanine residues are key structural requirements for its protective efficacy against initial ZIKV infection. In summary, we demonstrate that Hc-CATH provides prophylactic and therapeutic efficacy against ZIKV infection via downregulation of AXL, as well as inactivating the virion. Our findings reveal a novel mechanism of cathelicidin against viral infection and highlight the potential of Hc-CATH to prevent and treat ZIKV infection.
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