Cathelicidin antimicrobial peptides suppress EV71 infection via regulating antiviral response and inhibiting viral binding
Cathelicidin antimicrobial peptides suppress EV71 infection via regulating antiviral response and inhibiting viral binding
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Cathelicidin 抗菌肽通过调节抗病毒反应和抑制病毒结合来抑制 EV71 感染
DOI：
10.1016/j.antiviral.2021.105021
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发表时间：
2021
影响因子：
7.6
通讯作者：
Lin Wei
中科院分区：
文献类型：
--
作者：
Jie Yu;Yue Dai;Yuxuan Fu;Kezhen Wang;Yang Yang;Min Li;Wei Xu;Lin Wei
Cathelicidin抗菌肽（人LL-37和小鼠CRAMP）主要对包膜病毒具有杀病毒作用。然而，LL-37和CRAMP对无包膜病毒的作用和相关机制尚不清楚。我们发现，新生ICR小鼠感染无包膜肠道病毒71（non-enveloped Enterovirus 71，EV 71）后，不同组织中CRAMP的表达显著上调，而EV 71的复制在CRAMP上调后逐渐下降，表明凯萨林菌素对EV 71具有抗病毒作用。体外抗病毒试验显示，LL-37和CRAMP可显著降低细胞病变效应（CPE）、细胞内病毒RNA拷贝数、病毒VP 1蛋白水平和细胞外病毒，表明LL-37和CRAMP显著抑制EV 71的复制。作用机制研究表明，LL-37和CRAMP对EV 71无杀病毒作用，但能显著调节U251细胞的抗病毒免疫应答。LL-37或CRAMP与U251细胞共孵育显著增加基础干扰素-β（IFN-β）表达和干扰素调节转录因子3（IRF 3）磷酸化，适度增加EV 71感染后IFN-β产生和IRF 3磷酸化，并显著降低EV 71感染后白细胞介素-6（IL-6）产生和p38丝裂原活化蛋白激酶（MAPK）活化。此外，LL-37和CRAMP直接抑制病毒与U251细胞的结合。LL-37和CRAMP共同通过调节抗病毒应答和抑制病毒结合而显著抑制EV 71复制，为针对EV 71感染的肽药物开发提供了有效的候选物。
Cathelicidin antimicrobial peptides (human LL-37 and mouse CRAMP) are mainly virucidal to enveloped virus. However, the effects and relative mechanisms of LL-37 and CRAMP on non-enveloped virus are elusive. We herein found that CRAMP expression was significantly up-regulated post non-enveloped Enterovirus 71 (EV71) infection in different tissues of newborn ICR mice, while EV71 replication gradually declined post CRAMP up-regulation, indicating the antiviral potential of cathelicidin against EV71.In vitroantiviral assay showed that LL-37 and CRAMP markedly reduced cytopathic effects (CPE), intracellular viral RNA copy numbers, viral VP1 protein levels, and extracellular virons in U251 cells post EV71 infection, indicating that LL-37 and CRAMP significantly inhibited EV71 replication. Mechanism of action assay showed that LL-37 and CRAMP were not virucidal to EV71, but markedly regulated antiviral immune response in U251 cells. Co-incubation of LL-37 or CRAMP with U251 cells markedly increased the basal interferon-β (IFN-β) expression and interferon regulatory transcription factor 3 (IRF3) phosphorylation, modestly enhanced IFN-β production and IRF3 phosphorylation upon EV71 infection, and significantly reduced interleukin-6 (IL-6) production and p38 mitogen-activated protein kinase (MAPK) activation post EV71 infection. Additionally, LL-37 and CRAMP directly inhibited viral binding to U251 cells. Collectively, LL-37 and CRAMP markedly inhibited EV71 replication via regulating antiviral response and inhibiting viral binding, providing potent candidates for peptide drug development against EV71 infection.