Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
J Virol. 2020 Jun 16;94(13). doi: 10.1128/JVI.00274-20.
Chikungunya virus (CHIKV) is an important reemerging human pathogen transmitted by mosquitoes. The virus causes an acute febrile illness, chikungunya fever, which is characterized by headache, rash, and debilitating (poly)arthralgia that can reside for months to years after infection. Currently, effective antiviral therapies and vaccines are lacking. Due to the high morbidity and economic burden in the countries affected by CHIKV, there is a strong need for new strategies to inhibit CHIKV replication. The serotonergic drug 5-nonyloxytryptamine (5-NT) was previously identified as a potential host-directed inhibitor for CHIKV infection. In this study, we determined the mechanism of action by which the serotonin receptor agonist 5-NT controls CHIKV infection. Using time-of-addition and entry bypass assays, we found that 5-NT predominantly inhibits CHIKV in the early phases of the replication cycle, at a step prior to RNA translation and genome replication. Intriguingly, however, no effect was seen during virus-cell binding, internalization, membrane fusion and genomic RNA (gRNA) release into the cell cytosol. In addition, we show that the serotonin receptor antagonist methiothepin mesylate (MM) also has antiviral properties toward CHIKV and specifically interferes with the cell entry process and/or membrane fusion. Taken together, pharmacological targeting of 5-HT receptors may represent a potent way to limit viral spread and disease severity. The rapid spread of mosquito-borne viral diseases in humans puts a huge economic burden on developing countries. For many of these infections, including those caused by chikungunya virus (CHIKV), there are no specific treatment possibilities to alleviate disease symptoms. Understanding the virus-host interactions that are involved in the viral replication cycle is imperative for the rational design of therapeutic strategies. In this study, we discovered an antiviral compound, elucidated its mechanism of action, and propose serotonergic drugs as potential host-directed antivirals for CHIKV.
基孔肯雅病毒（CHIKV）是一种通过蚊子传播的重要的新兴人类病原体。该病毒引起急性发热疾病，即基孔肯雅热，其特征为头痛、皮疹和使人虚弱的（多）关节炎，感染后可持续数月至数年。目前，尚无有效的抗病毒疗法和疫苗。由于受 CHIKV 影响的国家发病率和经济负担高，因此强烈需要新的策略来抑制 CHIKV 复制。血清素能药物 5-壬氧基色胺（5-NT）先前被鉴定为抑制 CHIKV 感染的潜在宿主定向抑制剂。在这项研究中，我们确定了血清素受体激动剂 5-NT 控制 CHIKV 感染的作用机制。通过时间添加和进入旁路测定，我们发现 5-NT 主要在复制周期的早期阶段抑制 CHIKV，即在 RNA 翻译和基因组复制之前的步骤。然而，有趣的是，在病毒-细胞结合、内化、膜融合和基因组 RNA（gRNA）释放到细胞质中时，没有观察到作用。此外，我们表明，血清素受体拮抗剂甲硫哒嗪甲磺酸盐（MM）也对 CHIKV 具有抗病毒特性，并且特异性干扰细胞进入过程和/或膜融合。总之，对 5-HT 受体的药理学靶向可能是限制病毒传播和疾病严重程度的有效方法。蚊媒病毒病在人类中的迅速传播给发展中国家带来了巨大的经济负担。对于许多此类感染，包括基孔肯雅病毒（CHIKV）引起的感染，没有特定的治疗方法可以缓解疾病症状。了解病毒-宿主相互作用在病毒复制周期中是必不可少的，这对于合理设计治疗策略至关重要。在这项研究中，我们发现了一种抗病毒化合物，阐明了其作用机制，并提出了血清素能药物作为 CHIKV 的潜在宿主定向抗病毒药物。
