In December 2019, the previously unknown Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus spread among the population of Wuhan, China. The rapid global advance of the virus and the thousands of deaths caused by coronavirus disease (COVID-19) have prompted the World Health Organization (WHO) to declare a state of pandemic on 12 March 2020 ^[1][2][3][1,2,3].

With a re-emerging pathogen such as the SARS-CoV-2, it remains absolutely necessary to gain a better understanding of the precise mechanisms of the SARS-CoV-2 pathophysiology and future viral variants [4]. In this context, the host immune response to the virus appears to play a key role in the disease pathogenesis and clinical presentation. An excessive inflammatory reaction, characterized by a marked pro-inflammatory cytokine release, is remarkable in patients with severe COVID-19. Thus, leading to immune abnormalities which may lead to persisted infections and septic shock ^[5][6][7][5,6,7].

Coronavirus has a 5′cap structure and 3′polyA tail. The spike glycoprotein (S), envelope (E), membrane (M) and nucleocapsid (N) are structural proteins in coronaviruses. S protein is cleaved to S1 and S2 subunits. S2 facilitates the entry into target cells ^[8][9][10][8,9,10]. A major host protease, named transmembrane serine protease 2 (TMPRSS2), enables SARS-CoV-2 entry into host cells by priming the spike protein. SARS-CoV-2 uses the angiotensin converting enzyme 2 (ACE2) as a receptor for host cell attachment; once attached, the viral spike protein is cleaved by TMPRSS2 to allow fusion of the viral and cellular membranes ^[11][12][11,12]. The host protease TMPRSS2 plays a critical role in facilitating SARS-CoV-2 entry into host cells by priming the viral spike protein. Once the spike protein attaches to the host receptor ACE2, TMPRSS2 cleaves it, allowing fusion of the viral and cellular membranes. This process enables viral entry and subsequent replication, leading to the development of COVID-19. However, in some individuals, a dysregulated immune response occurs, resulting in a cytokine storm. This immune response involves the release of large amounts of pro-inflammatory cytokines and chemokines by immune effector cells, which can cause severe damage to host tissues and organs. The dysregulated immune response and cytokine storm are major causes of death in COVID-19. Therefore, TMPRSS2 may play a role not only in viral entry but also in the development of cytokine storm [13].

In a cytokine storm, the immune system produces an excessive amount of pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), among others. These cytokines can cause widespread inflammation throughout the body, which can lead to tissue damage and organ failure. In COVID-19, the cytokine storm is thought to contribute to the development of acute respiratory distress syndrome (ARDS), which is a severe lung condition that can lead to respiratory failure [14]. IL-6 is also involved in systemic inflammation during infection, which is probably influenced by pre-existing comorbidities [15]. This is followed by the infiltration of macrophages and neutrophils into the lung tissue, which results in a cytokine storm ^[16][17][18][16,17,18]. According to Jiang et al. (2022), further studies are still needed to fully elucidate the mechanism behind the cytokine storm induced by SARS-CoV-2 infection and thus provide new targets for therapeutic interventions [19].

The NF-κB signal transduction pathway is a common pathway centrally involved in the generation of pro-inflammatory cytokine and chemokine cascades in COVID-19 ^[20][21][22][20,21,22]. Inhibition of the NF-κB pathway increased survival rates in mice infected with SARS-CoV, due the fact that NF-κB signaling pathway activation is one of the major contributions to the inflammation induced upon SARS-CoV infection [23]. On a more molecular level, increased NF-κB activity leads to increased expression of Lin28, a gene that encodes an RNA-binding protein that plays a key role in regulating gene expression and developmental processes in many organisms, including humans. Lin28 has been shown to inhibit the maturation of let-7 family miRNAs, miRNAs that normally inhibits NF-κB transcripts and activators such as IL-6 [24].

2. MicroRNA Let-7

MiRNA is a type of direct and potent regulator of gene expression. MiRNA controls gene expression by binding any regions suitable for interaction that can be located in DNA and RNA. The interplay between miRNA and other biomolecules is responsible for the homeostasis of a living organism ^[25][38]. Many aspects of the miRNA let-7 intersect with the immunopathology of COVID-19. The present review identified six experiments testing hypotheses about the role of let-7 in COVID-19 pathology, and these were critically summarized in the present article. Only two of these have been performed in humans. The Wang Y. et al. trial has the advantage of having dichotomous groups and recruiting patients from four different hospitals ^[26][34]. However, the low number of patients may influence the accuracy of the results. Regarding the findings of each study, the most frequent finding was the increased expression of pro-inflammatory cytokines, especially IL-6, correlated with the suppression of let-7, generating the mechanism for the cytokine storm ^[26][27][28][33,34,35]. These findings are consistent with the literature of miRNA let-7 ^[25][38]. Most of the studies assessed were laboratory-based. They showed plausible correlations between aspects of COVID-19 immunopathology with let-7. Increased expression of TMPRSS2 via repression of let-7 was cited by two authors ^[28][29][31,35]; this implies an increase in viral uptake into the target cells via two mechanisms: by the cleavage of SARS-S, which activates the S protein for membrane fusion, and by the cleavage of ACE2 ^[30][31][39,40]. The internalization and replication of virus subsequently causes degradation of membrane-bound ACE2 receptors, which in turn causes increase in angiotensin II and the angiotensin type 1 receptor, resulting in an inflammatory immune response ^[32][41]. Thus, decreased let-7 expression may play a role in increasing the viral load of the disease by facilitating virus entry into the host cells through increased expression of TMPRSS2. The let-7 suppression also leads to increased activation of the TLR4/NF-κB pathway ^{[27][33][34][35]}[33,42,43,44]. Activated NF-κB transcription factors are a trigger for the expression of a wide variety of cytokines, (e.g., IL-1, IL-2, IL-6 and TNF-α) that can induce an inflammatory programming in resident macrophages and recruit activated monocytes and T cells to the lungs ^[36][37][45,46]. In addition, one of the most highly induced NF-κB-dependent cytokines is IL-6; in patients with COVID-19, elevated IL-6 levels are associated with worse clinical outcomes ^[38][47]. Activation of NF-κB promotes the synthesis of the microRNA binding protein LIN-28, which reduces the synthesis of mature let-7, thus constituting an inflammatory loop involving NF-κB/IL-6/let-7/ACE2 ^[39][40][48,49]. These findings are plausible to explain the hyperinflammatory state and cytokine storm induced in severe cases of the disease, which results in tissue damage, acute respiratory distress (ARDS) and multiple organ failure ^[41][42][50,51]. Furthermore, overexpression of let-7 is able to suppress the hyperinflammatory state. Discovered by Xie C., C1632 is a small molecule that serves as a let-7 stimulator, capable of positively regulating let-7 and therefore reducing viral replication and the secretion of pro-inflammatory cytokines. This molecule had attractive results in in vitro studies as a potential therapeutic for COVID-19 ^[43][32]. Like C1632, other therapeutic targets may have therapeutic potential through the regulation of let-7, and this is an attractive biomarker for future therapeutic research.