Yang Alexander, Guduguntla Lakshmi S, Yang Bing
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 3939 Woodward Ave, Detroit, MI 48202, USA.
Wayne State School of Medicine, 540 E Canfield St, Detroit, MI 48201, USA.
J Cell Immunol. 2020;2(6):333-340. doi: 10.33696/immunology.2.063.
The symptoms of the COVID-19 range from asymptomatic or mild disease to severe disease that results in acute respiratory distress syndrome (ARDS) and eventually death. Understanding the molecular mechanisms responsible for the progression from mild to severe disease is the key to decreasing the mortality of COVID-19. Compared to mild cases, severe cases of the COVID-19 have decreased interferon (IFN) α, β, λ production. Type I (IFN α/β) and III IFNs (λ) work coordinately to induce inhibition of viral reproduction through the stimulation of interferon stimulated genes (ISGs). Failure to mount an IFN response leads to suboptimal activation of adaptive immune response and increased viral load. The increased viral load causes severe tissue damage, inducing a late wave of IFNs and an exacerbated inflammatory response. There are two known risk factors associated with severe disease- obesity and aging. Both lead to the activation of inflammasome NLRP3, which stimulates transcription factor NFκB and the production of inflammatory cytokines. Type I IFNs inhibit activation of NRLP3. Taken together, an early deficient IFN response and the following hyperinflammatory state are the hallmarks of severe COVID-19. This suggests that both type I and III IFNs could potentially be beneficial as prophylaxis and treatment of COVID-19 at the early stage of infection. Indeed, clinical studies have shown benefit of IFN Is, and there are ongoing trials testing type III IFNs for the treatment of COVID-19. Another strategy is to use hydroxychloroquine (HCQ) to inhibit the viral entry into the cells. Our reanalysis of the results from two randomized clinical trials (RCTs) has concluded that use of HCQ is beneficial in postexposure prophylaxis. These two strategies can have great potential in the current pandemic of COVID-19.
新冠病毒病（COVID-19）的症状范围从无症状或轻症到导致急性呼吸窘迫综合征（ARDS）并最终死亡的重症。了解从轻症发展到重症的分子机制是降低COVID-19死亡率的关键。与轻症病例相比，COVID-19重症病例的干扰素（IFN）α、β、λ产生减少。I型（IFNα/β）和III型IFN（λ）协同作用，通过刺激干扰素刺激基因（ISG）来诱导抑制病毒复制。无法产生IFN反应会导致适应性免疫反应的激活不足，并增加病毒载量。病毒载量增加会导致严重的组织损伤，引发后期的IFN浪潮和加剧的炎症反应。有两个已知的与重症相关的风险因素——肥胖和衰老。两者都会导致炎性小体NLRP3的激活，从而刺激转录因子NFκB并产生炎性细胞因子。I型IFN抑制NRLP3的激活。综上所述，早期的IFN反应缺陷和随后的高炎症状态是重症COVID-19的特征。这表明I型和III型IFN在感染的早期阶段作为COVID-19的预防和治疗手段可能都有益处。事实上，临床研究已显示IFN-I的益处，并且正在进行试验以测试III型IFN用于治疗COVID-19。另一种策略是使用羟氯喹（HCQ）来抑制病毒进入细胞。我们对两项随机临床试验（RCT）结果的重新分析得出结论，使用HCQ在暴露后预防中是有益的。这两种策略在当前的COVID-19大流行中可能具有巨大潜力。
