Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina 86057-970, PR, Brazil.
Laboratory of Molecular Virology, Carlos Chagas Institute/Fiocruz PR, Curitiba 81310-020, PR, Brazil.
Cells. 2023 Feb 9;12(4):556. doi: 10.3390/cells12040556.
Chikungunya virus is an arthropod-borne infectious agent that causes Chikungunya fever disease. About 90% of the infected patients experience intense polyarthralgia, affecting mainly the extremities but also the large joints such as the knees. Chronic disease symptoms persist for months, even after clearance of the virus from the blood. Envelope proteins stimulate the immune response against the Chikungunya virus, becoming an important therapeutic target. We inactivated the Chikungunya virus (iCHIKV) and produced recombinant E2 (rE2) protein and three different types of anti-rE2 monoclonal antibodies. Using these tools, we observed that iCHIKV and rE2 protein induced mechanical hyperalgesia (electronic aesthesiometer test) and thermal hyperalgesia (Hargreaves test) in mice. These behavioral results were accompanied by the activation of dorsal root ganglia (DRG) neurons in mice, as observed by calcium influx. Treatment with three different types of anti-rE2 monoclonal antibodies and absence or blockade (AMG-9810 treatment) of transient receptor potential vanilloid 1 (TRPV1) channel diminished mechanical and thermal hyperalgesia in mice. iCHIKV and rE2 activated TRPV1+ mouse DRG neurons in vitro, demonstrating their ability to activate nociceptor sensory neurons directly. Therefore, our mouse data demonstrate that targeting E2 CHIKV protein with monoclonal antibodies and inhibiting TRPV1 channels are reasonable strategies to control CHIKV pain.
基孔肯雅热病毒是一种节肢动物传播的传染性病原体，可引起基孔肯雅热疾病。约 90%的感染患者会出现剧烈的多关节炎，主要影响四肢，但也会影响膝盖等大关节。慢性疾病症状会持续数月，即使病毒从血液中清除后也是如此。包膜蛋白刺激针对基孔肯雅热病毒的免疫反应，成为重要的治疗靶点。我们使基孔肯雅热病毒（iCHIKV）失活，并产生重组 E2（rE2）蛋白和三种不同类型的抗-rE2 单克隆抗体。使用这些工具，我们观察到 iCHIKV 和 rE2 蛋白在小鼠中诱导机械性痛觉过敏（电子压痛计测试）和热痛觉过敏（Hargreaves 测试）。这些行为结果伴随着小鼠背根神经节（DRG）神经元的激活，如钙内流观察到的那样。用三种不同类型的抗-rE2 单克隆抗体和瞬时受体电位香草酸 1（TRPV1）通道的缺失或阻断（AMG-9810 治疗）处理，可减轻小鼠的机械性和热痛觉过敏。iCHIKV 和 rE2 在体外激活 TRPV1+小鼠 DRG 神经元，证明它们能够直接激活伤害感受器感觉神经元。因此，我们的小鼠数据表明，用单克隆抗体靶向 E2 基孔肯雅热病毒蛋白和抑制 TRPV1 通道是控制基孔肯雅热疼痛的合理策略。
