SARS-CoV-2 is a positive single-stranded RNA (ssRNA) virus belonging to Betacoronavirus genus, coronaviridae family. It has a large genome of 29.9kb within 13 open reading frames (ORFs). ORF1a and ORF1b permit the primary translation of a polyprotein to initiate infection (Kim et al., 2020). Subsequently, after some replications, the other ORFs assure the expression of the subgenomic mRNA encoding for all structural proteins (Sola et al., 2015). Until now, SARS-CoV-2 is provoking infection resulting in human’s hospitalization and death worldwide. The most people at risk are the ones with advanced age, hypertension, cardiovascular disease and diabetes (Wang et al., 2020). The main targets for antiviral development are RNA-dependent RNA-polymerase (RdRp), viral proteases or ACE-2 cell receptors (Kruse, 2020; Majumder and Minko, 2021). However, their progress in FDA approval is challenging due to their moderate effect and the rapid emergence of new virus variants (Robinson et al., 2022). Similarly, vaccines are being put into use by some commercial companies such as Jonhson & Johnson or Sinovac Biotech but their immune protection efficacy is far from satisfactory due to the fast evolution of SARS-CoV-2 (Hadj Hassine, 2022). COVID-19 symptoms are mild and self-limiting or in many cases asymptomatic. However, some of the infected people may develop severe symptoms which can lead to death (Huang et al., 2020). Indeed, it has infected 700 million people so far with 6.8 million deaths (COVID-19 Map - Johns Hopkins Coronavirus Resource Center (jhu.edu), access on 09.03.2023). Studies have proven that many severe cases are due to inappropriate hyperinflammatory responses of the immune system to the viral infection (Kaivola et al., 2021; Vora et al., 2021). In fact, immune system responses are the first line of defense against viral infection. Once the spike (S) protein of SARS-CoV-2 binds to the cell receptors, pattern-recognition receptors such as Nod-like receptor (NLR) or absent in melanoma-2 (AIM2) will assemble inflammasomes through inducing membrane pore formation and activation of proinflammatory cytokines in order to activate cell death and eliminate the viral infection ( Figure 1 ). Indeed, during SARS-CoV-2 infection, those proteins are highly promoted. Therefore, the over-responses induce lung injuries leading to severe symptoms including acute respiratory distress syndrome (ARDS) and subsequent death (Lee et al., 2020). Thus, controlling this response of the immune system is essential and represents a valuable key for the fight against COVID-19 leading to severe symptoms (Yap et al., 2020; Rodrigues et al., 2021). This review highlights the involved inflammasomes during SARS-CoV-2 infection and summarizes their corresponding inhibitors. Consequently, the information presented would be helpful in the understanding of viral pathogenesis mechanism, the understanding of inflammasome roles during SARS-Cov-2 infection and development of novel therapeutic molecules against COVID-19. Moreover, it provides insights on future study direction of the virus as it is quite new and a lot remain unknown.

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. NLRP3 is the most studied inflammasome and the first known to be activated during SARS-CoV-2 infection (Freeman and Swartz, 2020). However, other inflammasomes such as NLRP1, AIM2, caspase-4 and -8 have a quite high possibility of involvement in activating cytokines that induce the over-responses of the immunity and the severity of the disease.

Multiple variants of SARS-Cov-2 have been emerging since its first apparition in Wuhan at the end of 2019. The virus has adapted quickly to humans and became highly mutated mostly at its spike protein sequence which is responsible of the attachment of the virus to ACE-2 cell surface receptor (Awadasseid et al., 2021; Harvey et al., 2021). To date, 5 of the existing variants are considered VOCs or variant of concerns by World Health Organization (WHO). VOCs have a high transmission rate compared to others: rapid spread and quick circulating dominance. In fact, most times, when a new variant emerges, the old one is no longer circulating. They are Alpha, Beta, Gamma and O’micron variants (Scovino et al., 2022). Their direct relation on how they handle immune responses including inflammasome is not yet elucidated. Through early studies on this new virus, inflammasome was positively correlated to lead the viral infection into severe disease by over-secreting cytokines and thus provoke tissue damages and reduce clinical outcomes ( Figure 1 ) (Li et al., 2020; Junqueira et al., 2021; Kaivola et al., 2021; Vora et al., 2021). In fact, each variant has different transmission rate and pathogenicity (Kumar et al., 2022). It may be due to cross-protections acquired during past infection or for people that were vaccinated. Interestingly, studied showed that vaccinated people with the first strain Wuhan-hu have protection against Alpha, Beta and Gamma variant but not for O’micron which has more than 15 mutations at the spike receptor binding domain (RBD) plus multiple deletions and substitutions in the N-terminal (Cameroni et al., 2022; Zeng et al., 2022). Furthermore, a study in UK showed that there was a T cell strong memory in patients infected with SARS-Cov-2. Concerning the inflammasome response to SARS-Cov-2 new variants, deeper studies are in need to further confirm the statement of previous studies that obviously showed correlation of inflammasomes and severe COVID-19 (Peng et al., 2020). Hence, investigating the relationship between inflammasomes and the different VOCs will ultimately give more understanding on how the organism reacts towards the infection and how to limit occurrence of severe cases. Furthermore, NLRP3 inflammasome which is the most related to SARS-Cov-2 has different variants as well. Study proved that NLRP3 variants are also responsible of different responses and then clinical symptoms: severe or mild. Indeed, NLRP3 rs10157379 and rs10754558 are the ones positively related to severe COVID-19 (Maes et al., 2022).

As a major class of anti-inflammatory molecules, series of compounds targeting a certain type of inflammasome are currently in the preclinical and clinical stages, and their indications include some non-infectious diseases such as atherosclerosis, Alzheimer, Parkinson, gout, rheumatoid arthritis and non-alcoholic steatohepatitis (Awadasseid et al., 2021; Harvey et al., 2021). For infectious diseases like SARS-CoV-2 infection, people may be worried whether the blockage of IL-1 increases the risk of infection. After all, cytokines are natural protein that the organism needs to protect against pathogens. However, the risk shall be reduced as there are multiple ways that innate immune response use to produce IL-1 during infection. Therefore, it makes NLRP3 the most attractive inflammasome to target (Awadasseid et al., 2021; Harvey et al., 2021). To date, there are no commercialized inflammasome inhibitors specifically applied for the treatment of SARS-CoV-2 infection (Declercq et al., 2022). Nevertheless, several existing ones for other diseases are being tested for COVID-19. The results seem encouraging, which brings a glimmer of hope for conquering COVID-19 induced ARDS. We summarize them herein after ( Table 1 ).

Measures taken towards SARS-CoV-2 pandemic such as restrictions have been removed in almost all countries. However, until now, SARS-CoV-2 is continuing to provoke severe diseases and even death in the world (Chu et al., 2022; Fox et al., 2022). Indeed, finding a powerful and thorough treatment mostly for those leading to severe COVID-19 disease is still an ultimate goal that has to be reached as soon as possible. Moreover, the emergence of new variant of concerns are worrying as they become highly contagious and may lead to a new pandemic wave. Targeting inflammasome, an intracellular protein complex activated in innate immune response following antigen attacks, has been becoming more and more attractive with the increasing investment of many large pharmaceutical companies. Actually, series of inflammasome inhibitors are being tested in the pre- and clinical stages for the treatment of several non-infectious diseases such as CAPS, gouty arthritis, type 2 diabetes etc. For infectious disease like SARS-CoV-2 infection, the cause of cytokine storm is believed due to an excessive immune responses in the organism but not the virus itself (Kaivola et al., 2021). Multiple inflammasomes already exist within the organism and there are multiple alternative ways to produce IL-1 according to the pathogen (virus, bacteria…). Thus, blocking one inflammasome by its inhibitor does not increase the risk of infection and shall not affect the level of innate immune responses. Hence, it represents the best way to fight the infection. In fact, some NLRP3 inhibitors being evaluated under experimental studies have already showed quite satisfactory results (Freeman and Swartz, 2020; Declercq et al., 2022). Besides NLRP3, other types of inflammasomes that were initially known to interact with dsRNA or bacteria such as AIM-2, caspase-4 and -8 were found to play a role in the inflammation responses during COVID-19. Thus, this wide range of molecules represents a broad target spectrum that is likely to be used to develop therapeutics to fight SARS-CoV-2 induced acute lung injury. Therefore, the symptoms may be greatly alleviated through the application of a direct antiviral combined with an inflammasome inhibitor. Nevertheless, further clinical trials have to be carried out to confirm this statement. To ensure the safety of such anti-inflammatory drugs, other non-identified inflammasome that might exist and counteract with SARS-Cov-2 has to be taken in consideration. Moreover, NLRP3 inhibitors does not only suppresses IL-1 but IL-18 as well which is an important regulator for the innate system. This fact may produce an unexpected pathophysiological consequences through a complicated immune network. However, the development of inflammasome inhibitors still hold a promise to treat severe COVID-19 syndrome effectively and eventually reduce mortality.

KH, RD: conceptualization, literature review, critical and comparative analysis of available information. RD: original manuscript writing and figure preparation. KH: supervision, revision and funding acquisition. YW, DH: comments and suggestion. All authors contributed to the article and approved the submitted version.