PDF(Pubmed)
Abstract：
The late 2019 emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, caused profound and unprecedented disruption to the global socio-economic structure, negatively affecting millions of lives worldwide. A typical hallmark of severe COVID-19 is hyper inflammation due to aberrant cytokine release (cytokine storm) by innate immune cells. Recent studies have revealed that SARS-CoV-2, through its spike (S) protein, can activate the body\'s innate immune cells via Toll-Like Receptors (TLRs), particularly TLR4. In silico studies have demonstrated that the S protein binds with high affinity to TLR4, triggering downstream signaling processes that result in pro-inflammatory cytokine release. Compared to other TLRs, such as TLR2, TLR4 plays a more significant role in initiating and sustaining the inflammatory response associated with severe COVID-19. Furthermore, interactions between the virus and target cells can enhance the cellular expression of TLR4, making cells more susceptible to viral interactions and subsequent inflammation. This increased expression of TLR4 upon viral entry creates a feedback loop, where heightened TLR4 levels lead to amplified inflammatory responses, contributing to the severity of the disease. Additionally, TLR4\'s potent activation of inflammatory pathways sets it apart from other TLRs, underscoring its pivotal role in the pathogenesis of COVID-19. In this review, we thoroughly explore the multitude of regulatory signaling pathways that SARS-CoV-2 employs to incite inflammation. We specifically focus on the critical impact of TLR4 activation compared to other TLRs, highlighting how TLR4\'s interactions with the viral S protein can exacerbate the severity of COVID-19. By delving into the mechanisms of TLR4-mediated inflammation, we aim to shed light on potential therapeutic targets that could mitigate the inflammatory damage caused by severe COVID-19. Understanding the unique role of TLR4 in the context of SARS-CoV-2 infection could pave the way for novel treatment strategies that specifically inhibit this receptor\'s activity, thereby reducing the overall disease burden and improving patient outcomes.
摘要：
2019年末出现了严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2），COVID-19的致病因素对全球社会经济结构造成了深刻和前所未有的破坏，对全世界数百万人的生活产生负面影响。严重COVID-19的典型标志是由于先天免疫细胞的异常细胞因子释放(细胞因子风暴)引起的过度炎症。最近的研究表明，SARS-CoV-2通过其尖峰（S）蛋白，可以通过Toll样受体（TLRs）激活身体的先天免疫细胞，特别是TLR4。计算机模拟研究表明，S蛋白以高亲和力与TLR4结合，触发下游信号传导过程，导致促炎细胞因子释放。与其他TLR相比，如TLR2，TLR4在启动和维持与严重COVID-19相关的炎症反应中起着更重要的作用。此外，病毒与靶细胞之间的相互作用可以增强TLR4的细胞表达，使细胞对病毒相互作用和随后的炎症更敏感。这种增加的TLR4的表达在病毒进入创建一个反馈回路，TLR4水平升高导致炎症反应放大，导致疾病的严重程度。此外,TLR4对炎症途径的有效激活使其与其他TLRs区分开来，强调其在COVID-19发病机制中的关键作用。在这次审查中,我们彻底探索了SARS-CoV-2用于诱发炎症的多种调节信号通路.与其他TLRs相比，我们特别关注TLR4激活的关键影响，强调TLR4与病毒S蛋白的相互作用如何加剧COVID-19的严重程度。通过深入研究TLR4介导的炎症机制，我们的目标是阐明可能减轻严重COVID-19引起的炎症损伤的潜在治疗靶点。了解TLR4在SARS-CoV-2感染背景下的独特作用可以为特异性抑制该受体活性的新型治疗策略铺平道路。从而降低总体疾病负担并改善患者预后。
