Causes of mortality from COVID-19 include respiratory failure, heart failure, and sepsis/multiorgan failure. TLR4 is an innate immune receptor on the cell surface that recognizes pathogen-associated molecular patterns (PAMPs) including viral proteins and triggers the production of type I interferons and proinflammatory cytokines to combat infection. It is expressed on both immune cells and tissue-resident cells. ACE2, the reported entry receptor for SARS-CoV-2, is only present on ~1-2% of the cells in the lungs or has a low pulmonary expression, and recently, the spike protein has been proposed to have the strongest protein-protein interaction with TLR4. Here, we review and connect evidence for SARS-CoV-1 and SARS-CoV-2 having direct and indirect binding to TLR4, together with other viral precedents, which when combined shed light on the COVID-19 pathophysiological puzzle. We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signalling to increase cell surface expression of ACE2 facilitating entry. SARS-CoV-2 also destroys the type II alveolar cells that secrete pulmonary surfactants, which normally decrease the air/tissue surface tension and block TLR4 in the lungs thus promoting ARDS and inflammation. Furthermore, SARS-CoV-2-induced myocarditis and multiple-organ injury may be due to TLR4 activation, aberrant TLR4 signalling, and hyperinflammation in COVID-19 patients. Therefore, TLR4 contributes significantly to the pathogenesis of SARS-CoV-2, and its overactivation causes a prolonged or excessive innate immune response. TLR4 appears to be a promising therapeutic target in COVID-19, and since TLR4 antagonists have been previously trialled in sepsis and in other antiviral contexts, we propose the clinical trial testing of TLR4 antagonists in the treatment of severe COVID-19. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4.

中文翻译：

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COVID-19 和 Toll 样受体 4 (TLR4)：SARS-CoV-2 可能结合并激活 TLR4 以增加 ACE2 表达，促进进入并引起过度炎症


COVID-19 导致的死亡原因包括呼吸衰竭、心力衰竭和败血症/多器官衰竭。 TLR4 是细胞表面的先天免疫受体，可识别包括病毒蛋白在内的病原体相关分子模式 (PAMP)，并触发 I 型干扰素和促炎细胞因子的产生以对抗感染。它在免疫细胞和组织驻留细胞上表达。 ACE2 是报道的 SARS-CoV-2 的进入受体，仅存在于肺部约 1-2% 的细胞上或肺部表达较低，而最近，刺突蛋白被认为具有最强的蛋白 -与 TLR4 的蛋白质相互作用。在这里，我们回顾并连接了 SARS-CoV-1 和 SARS-CoV-2 与 TLR4 直接和间接结合的证据，以及其他病毒先例，这些证据结合起来揭示了 COVID-19 的病理生理学难题。我们提出了一个模型，其中 SARS-CoV-2 刺突糖蛋白结合 TLR4 并激活 TLR4 信号传导，以增加 ACE2 的细胞表面表达，从而促进进入。 SARS-CoV-2 还会破坏分泌肺表面活性剂的 II 型肺泡细胞，肺表面活性剂通常会降低空气/组织表面张力并阻断肺部的 TLR4，从而促进 ARDS 和炎症。此外，SARS-CoV-2 引起的心肌炎和多器官损伤可能是由于 TLR4 激活、异常 TLR4 信号传导和 COVID-19 患者的过度炎症所致。因此，TLR4在SARS-CoV-2的发病机制中发挥着重要作用，其过度激活会导致先天免疫反应延长或过度。 TLR4 似乎是 COVID-19 的一个有前途的治疗靶点，并且由于 TLR4 拮抗剂之前已在脓毒症和其他抗病毒环境中进行过试验，因此我们建议对 TLR4 拮抗剂在治疗重症 COVID-19 中进行临床试验。此外，正在进行的肺表面活性剂治疗 COVID-19 的临床试验也带来了希望，因为它们也能阻断 TLR4。