Department of Respiratory Medicine, The First People's Hospital of Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
National and Local Engineering Center for Infectious Biological Products, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China.
Virus Res. 2024 Jul;345:199386. doi: 10.1016/j.virusres.2024.199386. Epub 2024 May 6.
Coxsackievirus A16 (CV-A16) and coxsackievirus A10 (CV-A10), more commonly etiological agents of hand, foot and mouth disease (HFMD), are capable of causing severe neurological syndromes with high fatalities, but their neuropathogenesis has rarely been studied. Mounting evidence indicated that pyroptosis is an inflammatory form of cell death that might be widely involved in the pathogenic mechanisms of neurotropic viruses. Our study was designed to examine the effects of NLRP3-mediated pyroptosis in CV-A16- and CV-A10-induced inflammatory neuropathologic formation. In this work, it was showed that SH-SY5Y cells were susceptible to CV-A16 and CV-A10, and meanwhile their infections could result in a decreasing cell viability and an increasing LDH release as well as Caspase1 activation. Moreover, CV-A16 and CV-A10 infections triggered NLRP3-mediated pyroptosis and promoted the release of inflammatory cytokines. Additionally, activated NLRP3 accelerated the pyroptosis formation and aggravated the inflammatory response, but inhibited NLRP3 had a dampening effect on the above situation. Finally, it was further revealed that NLRP3 agonist enhanced the viral replication, but NLRP3 inhibitor suppressed the viral replication, suggesting that NLRP3-driven pyroptosis might support CV-A16 and CV-A10 production in SH-SY5Y cells. Together, our findings demonstrated a mechanism by which CV-A16 and CV-A10 induce inflammatory responses by evoking NLRP3 inflammasome-regulated pyroptosis, which in turn further stimulated the viral replication, providing novel insights into the pathogenesis of CV-A16 and CV-A10 infections.
柯萨奇病毒 A16（CV-A16）和柯萨奇病毒 A10（CV-A10），通常是手足口病（HFMD）的病原体，能够引起严重的神经综合征，死亡率很高，但它们的神经发病机制很少被研究。越来越多的证据表明，细胞焦亡是一种炎症形式的细胞死亡，可能广泛涉及神经嗜性病毒的致病机制。我们的研究旨在研究 NLRP3 介导的细胞焦亡在 CV-A16 和 CV-A10 诱导的炎症性神经病理形成中的作用。在这项工作中，我们表明 SH-SY5Y 细胞易受 CV-A16 和 CV-A10 的感染，同时它们的感染会导致细胞活力下降、LDH 释放增加和 Caspase1 激活。此外，CV-A16 和 CV-A10 感染触发 NLRP3 介导的细胞焦亡，并促进炎症细胞因子的释放。此外，激活的 NLRP3 加速细胞焦亡的形成并加重炎症反应，但抑制 NLRP3 对上述情况有抑制作用。最后，进一步表明 NLRP3 激动剂增强了病毒复制，而 NLRP3 抑制剂抑制了病毒复制，表明 NLRP3 驱动的细胞焦亡可能支持 SH-SY5Y 细胞中 CV-A16 和 CV-A10 的产生。总之，我们的研究结果表明，CV-A16 和 CV-A10 通过激活 NLRP3 炎性小体调节的细胞焦亡引起炎症反应的机制，进而进一步刺激病毒复制，为 CV-A16 和 CV-A10 感染的发病机制提供了新的见解。
