Since the end of 2019/early 2020, a new disease emerged, described initially as an outbreak of viral pneumonia in individuals living in Wuhan, China (1). Researchers identified a new coronavirus as the pathogen causing the outbreak and named it as SARS-CoV-2 (2). The World Health Organization (WHO) called the associated coronavirus disease COVID-19 (3). Due to this fast dispersion around the world, on March 11, 2020, WHO raised COVID-19 to the category of a pandemic that is still ongoing (4). Globally, mortality and incidence of SARS-CoV-2 have increased rapidly. The Americas are the continents most affected by the COVID-19 pandemic now, with the United States of America (USA) and Brazil being the leaders in the numbers of cases to date (5). SARS-CoV-2 has already infected more than 230 million individuals worldwide, and 4.7 million patients have died, according to WHO (6). In Brazil, the first case was notified on February 26th, 2020, and the first community transmission was identified on March 13th, 2020. The country has accumulated more than 20 million reported cases, with more than 586,000 deaths as of September 13th, 2021 (6, 7).
COVID-19 has a broad spectrum of clinical manifestations, from asymptomatic to mild/moderate symptoms, to most critical forms, as a severe acute respiratory syndrome (SARS), thromboembolism, sepsis, multiple organ failure, and death (6). Though the risk of death due to the COVID-19 varies among the countries, age, comorbidities, and host genetic factors, the mechanisms underlying SARS-CoV-2 infection and its clinical evolution are still unclear (8, 9).
Once SARS-CoV-2 infects individuals, host factors are activated by the presence of the virus inside the cells. Pattern-recognition receptors (PRR), recognize conserved virus fragments, known as pathogen-associated molecular patterns (PAMP), and trigger the activation of several cellular components (10, 11). Among the large family of PRRs are NOD-like receptors (NLR), retinoic acid-inducible gene-I (RIG- I)-like receptors (RLRs) and, Toll-like receptors (TLRs) (12). Some studies have already shown that the RLRs family is an important PRR in the detection of coronaviruses (13, 14). Besides that, the NLR receptors stand out due to their wide recognition of intrinsic or extrinsic stimuli, operating principally as cytoplasmatic sensors (15). These receivers when activated lead to the NF-kB activation pathway, which culminates in the transcription of several molecules, such as gasdermin-D (GSDM-D), pro-IL-1b, and pro-IL-18, among others (16, 17). These released molecules cause a wave of local inflammation, involving increased secretion of proinflammatory cytokines and chemokines (e.g., IL-6, IFN-γ, CCL2, and CXCL10) (18, 19). These and other cytokines have already been observed to be increased in SARS-Cov-2 infection, especially in more severe cases (18, 20) .
The primary function of the NLR is to form a multiprotein complex, known as inflammasome. The inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses, which interact with several adapter proteins leading to the activation of caspase-1 and inducing the release of the proinflammatory cytokines IL-1ß and IL-18 (21). Different PRR (e.g., NLRP1 and NLRP3) can activate inflammasome assembly in response to specific stimuli, leading to inflammation and thrilling the innate immune response. Inflammasome activation is strictly regulated by endogenous host proteins (e.g., CARD8 and HSP90) and by a variety of transcriptional and post-transcriptional mechanisms (22). Inflammasomes belonging to the NLR are composed of at least three components: a protein sensor (e.g., NLRP1 and NLRP3), an inflammatory caspase (e.g., caspase-1 and caspase-11), and, finally, an adapter molecule containing a CARD domain (e.g., ASC) (23). It has been shown that proteins E, ORF3a e ORF8b from SARS-CoV activate NLRP3 inflammasome (15). Mutations in the inflammasome genes may lead to inflammatory disorders. For example, the constitutively IL-1β high levels contribute to chronic inflammation (24), including viral infections (25). SNPs in the NLRP3 gene were associated with a group of inflammatory disorders of genetic origin with the exaggerated secretion of IL-1β (26).
Studies have already observed the relationship between inflammasome activation and COVID-19 (12, 27–30). Inflammasome activation is one of the main theories for the explanation of the cytokine storm during COVID-19 causing severe disease (12, 30). NLRP3 activation in COVID-19 patients has already been described in tissues of COVID-19 patients. Additionally, higher levels of IL-18 and Casp1p20 (Inflammasome products) in COVID-19 patients were associated with severe disease (30). However, exploring the role of the inflammasomes in the SARS-CoV-2 infection is still needed due to the recent onset of this pathogen. Genetic factors contributing to the outcome of SARS-CoV-2 infection are still little known; recently, variants in the specific sites of the ACE2 and TMPRSS2 genes, as well as the ABO locus and fewer others gene targets were considered as genetic risk factors for COVID-19 outcomes (31–33). No variants in inflammasome genes have ever been associated with risk or protection for COVID-19. The search of risk and/or protection factors for COVID-19 is of relevance for clinical management. Thus, in the present study, we investigated the impact of 11 single-base polymorphisms (SNPs) of the NLRP3, CARD8, AIM2, CASP-1, IFI16, and IL-1β inflammasome genes in SARS-CoV-2 infected individuals.