Toll-Like Receptor Signaling in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Innate Immune Responses and the Potential Application Value of Toll-Like Receptor Immunomodulators in Patients With Coronavirus Disease 2019

Abstract

Toll-like receptors (TLRs) are key sensors that recognize the pathogen-associated molecular patterns (PAMPs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to activate innate immune response to clear the invading virus. However, dysregulated immune responses may elicit the overproduction of proinflammatory cytokines and chemokines, resulting in the enhancement of immune-mediated pathology. Therefore, a proper understanding of the interaction between SARS-CoV-2 and TLR-induced immune responses is very important for the development of effective preventive and therapeutic strategies. In this review, we discuss the recognition of SARS-CoV-2 components by TLRs and the downstream signaling pathways that are activated, as well as the dual role of TLRs in regulating antiviral effects and excessive inflammatory responses in patients with coronavirus disease 2019 (COVID-19). In addition, this article describes recent progress in the development of TLR immunomodulators including the agonists and antagonists, as vaccine adjuvants or agents used to treat hyperinflammatory responses during SARS-CoV-2 infection.

Keywords: COVID-19; SARS-CoV-2; Toll-like receptor; immunomodulator; innate immune response.

FIGURE 1

Toll-like receptor-mediated antiviral and inflammatory responses during SARS-CoV-2 infection. TLR1/2/6 and 4 localize to cell membrane, and TLR3, TLR7/8, and 9 localize to endosome surface. The viral proteins of SARS-CoV-2 signal through TLR2 and TLR4 to activate the adaptor MyD88, which subsequently signals via NF-κB and MAPK to promote the expression of proinflammatory cytokines. TLR4 also recruits the adapter protein TRIF, which activates the TRAF3, resulting the IRF3 activation to lead the production of type I and III IFN. The ssRNA or dsRNA replication intermediates of SARS-CoV-2 are recognized by TLR3 and TLR7/8, respectively. The TLR7/8 recruit MyD88, and TLR3 via TRIF molecule. The proinflammatory cytokines induced by DAMPs accumulating during SARS-CoV-2 infection are driven by the transcription factor NF-κB. MAL, MyD88 adapter-like; TRAF, tumor necrosis factor receptor-associated factor; TRIF, TIR-domain-containing adapter-inducing interferon-β; TRAM, TRIF-related adaptor molecule; IRAK1/4, interleukin-1 receptor associated kinase 1/4; TAK1, transforming growth factor β-activated kinase 1; TAB, TAK1-binding proteins; IKK, IkB kinase; TBK1, TANK-binding kinase 1; ERK1/2, extracellular signal-regulated kinases 1/2; JNK, c-Jun N-terminal kinase; AP-1, activating protein-1.