Algesic activity of the human coronavirus OC43 derived peptide

The human coronavirus OC43 is responsible for 15-30% of seasonal “common cold” infections with typically mild respiratory symptoms. We demonstrated that the coronavirus OC43 derived small peptide encoded by the viral p65 proteins may exhibit molecular mimicry with the pro-algesic fragment of Myelin Basic Protein (MBP). After intrasciatic injection, the p65-derived peptide induced robust pain hypersensitivity in rats lasting for up to 21 days. Transcriptomic analysis at day 21 revealed extensive spinal up-regulation of pro-nociceptive genes. Strikingly, genome-wide isoform switching due to activation of transcriptional start sites and alternative splicing events has occurred. We hypothesized that the coronavirus-derived peptides can dysregulate MBP function in the PNS/CNS and promote neuropathic chronic pain. Our findings offer paradigm-shifting mechanistic understanding of the viral origin of idiopathic neurological effects including chronic neuropathic pain, a condition currently refractory to therapeutic treatment. This new knowledge will lead to new diagnostic, prognostic, and therapeutic approaches to benefit patients with chronic pain.人类冠状病毒OC43可导致15%~30%的季节性“普通感冒”感染，通常仅引发轻微呼吸道症状。本研究证实，由冠状病毒OC43的p65蛋白编码的小肽，可能与髓鞘碱性蛋白（Myelin Basic Protein，MBP）的致痛片段存在分子模拟现象。经坐骨神经内注射该p65来源肽后，可在大鼠体内诱导长达21天的显著痛觉超敏反应。对感染后第21天的样本开展转录组分析显示，脊髓内的致痛基因出现广泛上调。尤为引人注目的是，全基因组范围内因转录起始位点激活与可变剪接事件引发的异构体转换已被观测到。我们提出假说：冠状病毒来源的肽可紊乱周围神经系统（Peripheral Nervous System，PNS）与中枢神经系统（Central Nervous System，CNS）内的MBP功能，并促进神经性慢性疼痛的发生。本研究结果为包括目前治疗抵抗的慢性神经性疼痛在内的特发性神经系统病症的病毒起源机制，提供了范式革新的机制性认知。这一新的研究成果将为慢性疼痛患者带来全新的诊断、预后与治疗策略。