Abstract
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TLRs recognize various ligands and induce the internal signaling pathways that lead to activation of some transcription factors involved in the transcription of proinflammatory cytokines, such as nuclear factor-κB (1). TLR3 recognizes double-strand RNAs, whereas TLR7 and TLR8 recognize single-strand RNAs (8,15). Based on the fact that COVID-19 contains positive RNA, as its genome, hence, TLRs may be considered as the main intracytoplasmic PRRs against COVID-19. In parallel with the hypothesis, it has been documented that mast cells, which express TLRs, are the main source of proinflammatory cytokines during infection with COVID-19 (10). Conti et al. also revealed that women were affected by COVID-19 less than men may be through different expression of TLRs, especially TLR7 and TLR8 (5).
Previous investigations demonstrated that using TLR3, TLR7, and TLR8 antagonists can be used against viral infections. For example, Isogawa et al. showed that using TLR3 agonists leads inhibition of HBV replication (7). Another investigation proved the potential roles played by TLR agonists to improve immune responses against viruses (14). These antagonists include bacterial-secreted proteins, natural or synthetic small molecules, antibodies against TLRs, and TLR-derived transmembrane peptides (12). In addition, TLR antagonists can modulate immune responses in immune-related diseases. For example, a phase 2a trial study on the psoriasis patients revealed that using IMO-3100, an antagonist of TLR7, significantly modulate immune responses and downregulate cytokine production in the patients (9). Another study reported that using a human microsatellite DNA-mimicking Oligodeoxynucleotides (ODN) can trigger TLR7 and then downregulate the corresponded intracellular signaling pathways (16). Zhao et al. also revealed that sunitinib, a tyrosine kinase inhibitor, significantly decreased TLR activation-induced cytokine storm (18). In addition, the roles played by TLR antagonists against viral infections have been documented by Patel et al. (11). Interestingly, Perrin-Cocon et al. demonstrated that TLR4 antagonist FP7 significantly decreased the lethal lipopolysaccharide (LPS)-induced cytokine production in the influenza infection (13). A study by Conti et al. revealed that interaction between COVID-19 and TLRs leads to activation of interleukin (IL)-1β (4). The investigators also reported that IL-37 can interfere with myeloid differentiation primary response 88, an adaptor protein in the TLR signaling pathways, to decrease production of proinflammatory cytokines, such as IL-1β, by TLRs (4). Thus, it appears that IL-37 can be considered as a TLR antagonist against COVID-19-related storm cytokine. Interestingly, another study demonstrated that using the drugs that suppress IL-1β is to be taken into consideration to treat COVID-19 (3). Therefore, it appears that targeting TLRs can be considered as a work hypothesis against COVID-19. However, based on our knowledge there are released many reports regarding the clinical trials using TLR antagonists to modulate cytokine storm in the COVID-19-infected patients.
Collectively, based on the fact that the COVID-19 pathogenesis aspects are yet to be clarified and there is not a potential and confirmed therapeutic strategy to manage COVID-19-related morbidity and mortality, it may be hypothesized that using TLR antagonists may be the potential therapeutic strategies against COVID-19 pathogenesis, as a work hypothesis and need to be investigated by the investigators immediately.