Current Understanding of the Innate Control of Toll-like Receptors in Response to SARS-CoV-2 Infection

Abstract

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, threatens the entire world. It has affected every aspect of life and increased the burden on both healthcare and socioeconomic systems. Current studies have revealed that excessive inflammatory immune responses are responsible for the severity of COVID-19, which suggests that anti-inflammatory drugs may be promising therapeutic treatments. However, there are currently a limited number of approved therapeutics for COVID-19. Toll-like receptors (TLRs), which recognize microbial components derived from invading pathogens, are involved in both the initiation of innate responses against SARS-CoV-2 infection and the hyperinflammatory phenotype of COVID-19. In this review, we provide current knowledge on the pivotal role of TLRs in immune responses against SARS-CoV-2 infection and demonstrate the potential effectiveness of TLR-targeting drugs on the control of hyperinflammation in patients with COVID-19.

The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity

“…However, many viruses (e.g., SARA-COV-2 or influenza virus) encode structural and non-structural viral proteins that ablate the IFN signaling pathways through interaction with other cellular signaling pathways. This usually results in invalid STAT that fails to form phosphorylated ISGF3 complex, further abolishing the expression of antiviral ISGs (Mazewski et al, 2020;Yin et al, 2020;Jung and Lee, 2021). This process is concluded as an evasion of the innate immune response.…”

Innate Immune Response in SARS-CoV-2 Infection

“…RLRs intracellular pattern recognition receptors which play a key role in the activation of innate immune system during viral infection. In fact, RLRs are cytoplasmatic RNA helicases involved in the sensing of non-self RNA [ 17 ], which include melanoma differentiation-associated protein 5 (MDA-5), retinoic acid-inducible gene I (RIG-I) and the Probable ATP-dependent RNA helicase DHX58 known as LGP2. RLRs are normally inactive in uninfected cells and become active in presence of viral RNA, leading to interferons production to control the infection.…”

“…ssRNA genome of SARS-CoV-2 has been reported to be recognized by specific TLRs (TLR3, TLR7, and TLR8), all localized on the endosomal membrane [ 18 , 19 ], and also by MDA-5 and RIG-I, which are able to sense intracellular double-stranded RNA (dsRNA) produced during the infection [ 17 ].…”

Cytokine producing ability of peripheral blood cells from COVID-19 patients after unspecific in vitro stimulation

“…Then, the host immune system recognizes the whole virus or its surface epitopes, eliciting the innate or adaptive immune response [3][4][5][6][7][8][9]. Pathogen recognition receptors (PRRs), mainly Toll-like receptors (TLRs) [10], are expressed in immune cells, fibroblasts, and epithelial cells, including type II pneumocytes in the airways. The activation of TLRs leads to the subsequent production of type I IFNs and inflammatory cytokines via the activation of nuclear factor-κB (NF-κB) [9,11].…”

“…In sepsis and non-infectious SIRS a paradoxically diminished ability of circulating leukocytes to produce cytokines upon ex vivo activation has already been shown [19]. Recently published studies have analyzed cytokine production by blood cells from COVID-19 patients upon non-specific in vitro stimulation with Toll-like receptor 7/8 (TLR 7/8) agonist and anti-CD3 antibody [18], anti-CD3/ anti-CD28 antibodies [10,16], superantigens, pokeweed mitogen or Concanavalin A [7], but the results are somewhat contradictory. The in vitro production of cytokines from peripheral blood cells of COVID-19 patients upon non-specific activation with phytohemagglutinin (PHA), a mitogenic lectin known to activate T cells in the presence of monocytes [21], has not been investigated so far.…”