Sino-German Biomedical Center, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China.
Front Cell Infect Microbiol. 2023 Jun 9;13:1218039. doi: 10.3389/fcimb.2023.1218039. eCollection 2023.
Corona Virus Disease 2019 (COVID-19) continues to be a burden for human health since its outbreak in Wuhan, China in December 2019. Recently, the emergence of new variants of concerns (VOCs) is challenging for vaccines and drugs efficiency. In severe cases, SARS-CoV-2 provokes inappropriate hyperinflammatory immune responses leading to acute respiratory distress syndrome (ARDS) and even death. This process is regulated by inflammasomes which are activated after binding of the viral spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2) receptor and triggers innate immune responses. Therefore, the formation of "cytokines storm" leads to tissue damage and organ failure. NOD-like receptor family pyrin domain containing 3 (NLRP3) is the best studied inflammasome known to be activated during SARS-CoV-2 infection. However, some studies suggest that SARS-CoV-2 infection is associated with other inflammasomes as well; such as NLRP1, absent in melanoma-2 (AIM-2), caspase-4 and -8 which were mostly found during dsRNA virus or bacteria infection. Multiple inflammasome inhibitors that exist for other non-infectious diseases have the potential to be used to treat severe SARS-CoV-2 complications. Some of them have showed quite encouraging results during pre- and clinical trials. Nevertheless, further studies are in need for the understanding and targeting of SARS-Cov-2-induced inflammasomes; mostly an update of its role during the new VOCs infection is necessary. Hence, this review highlights all reported inflammasomes involved in SARS-CoV-2 infection and their potential inhibitors including NLRP3- and Gasdermin D (GSDMD)-inhibitors. Further strategies such as immunomodulators and siRNA are also discussed. As highly related to COVID-19 severe cases, developing inflammasome inhibitors holds a promise to treat severe COVID-19 syndrome effectively and reduce mortality.
2019 年 12 月，中国武汉爆发了 2019 年冠状病毒病（COVID-19），至今仍对人类健康造成严重负担。最近，新出现的关切变异株（VOCs）对疫苗和药物的功效构成了挑战。在严重情况下，SARS-CoV-2 引发了不适当的过度炎症免疫反应，导致急性呼吸窘迫综合征（ARDS），甚至死亡。这个过程受到炎症小体的调节，炎症小体在病毒刺突（S）蛋白与细胞血管紧张素转换酶 2（ACE2）受体结合后被激活，并触发先天免疫反应。因此，“细胞因子风暴”的形成导致组织损伤和器官衰竭。NOD 样受体家族含 pyrin 结构域蛋白 3（NLRP3）是研究最充分的炎症小体之一，已知在 SARS-CoV-2 感染过程中被激活。然而，一些研究表明，SARS-CoV-2 感染也与其他炎症小体有关，如缺失黑色素瘤 2（AIM-2）、半胱天冬酶-4 和 -8，这些炎症小体主要在双链 RNA 病毒或细菌感染时被发现。针对其他非传染性疾病的多种炎症小体抑制剂有可能被用于治疗严重的 SARS-CoV-2 并发症。一些抑制剂在临床前和临床试验中表现出相当令人鼓舞的结果。然而，为了理解和靶向 SARS-CoV-2 诱导的炎症小体，还需要进一步的研究；特别是需要更新其在新的 VOCs 感染过程中的作用。因此，本综述强调了所有报道的与 SARS-CoV-2 感染相关的炎症小体及其潜在抑制剂，包括 NLRP3 和 Gasdermin D（GSDMD）抑制剂。还讨论了进一步的策略，如免疫调节剂和 siRNA。由于与 COVID-19 重症高度相关，开发炎症小体抑制剂有望有效治疗严重 COVID-19 综合征并降低死亡率。
