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.

Keywords: COVID-19; SARS-CoV-2; Toll-like receptor (TLR); cytokine storm; hyperinflammation.

Figure 1

SARS-CoV-2 replication cycle. Viral entry of SARS-CoV-2 is initiated by the recognition of the host cell receptor ACE2 via the RBD of the S glycoprotein. After binding to host cell receptors, SARS-CoV-2 enters cells by endocytosis or direct fusion with the plasma membrane. The host proteases TMPRSS2 and cathepsins B and L mediate the proteolytic cleavage of the S protein, triggering membrane fusion and viral genome release into the cytoplasm. The RTC carries out viral RNA synthesis in DMVs, and newly produced viral RNAs and proteins are delivered to SMVs for assembly of new viruses. Finally, virions are secreted by exocytosis. This figure was created by BioRender.com accessed on 10 September 2021 (BioRender, Toronto, ON, Canada).

Figure 2

SARS-CoV-2 recognition by Toll-like receptors (TLRs). TLRs are responsible for recognizing pathogen-associated molecular patterns (PAMPs) derived from invading pathogens. Surface TLR2 and TLR4 and intracellular TLR3, TLR7/8, and TLR9 are thought to be involved in the sensing of SARS-CoV-2 infection. Activated TLRs initiate downstream signaling pathways by recruiting adaptor molecules, such as MyD88 and TRIF, which results in the subsequent production of inflammatory cytokines and type I IFNs through transcription factors NF-κβ and IRFs. This figure was created by BioRender.com accessed on 10 September 2021 (BioRender, Toronto, ON, Canada).