Role of Toll-like receptors in the pathogenesis of COVID-19

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a pandemic since March 2020. The exact pathogenesis of SARS-CoV-2 and the role of each component of the innate and adaptive immune system is still unknown. However, available data from other coronavirus families, such as SARS-CoV and the Middle East respiratory syndrome and also new findings could be useful for a better understanding of SARS-CoV-2. Toll-like receptors (TLR) play an important role in recognition of viral particles and activation of the innate immune system. Activation of TLR pathways leads to secretion of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α, as well as type 1 interferon. Different TLRs, like TLR2, TLR3, TLR4, TLR6, TLR7, TLR8, and TLR9 are potentially important in COVID-19 infection. It is also worth mentioning that we should bear in mind both the beneficial and harmful effects of TLR in confronting COVID-19 infection. TLRs could be a potential target in controlling the infection in the early stages of disease and production of vaccine against SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; Toll-like receptors; cytokines.

Figure 1

Toll‐like receptor signaling pathways. TLR2/6 and 4 localize in the cell membrane, and TLR3, TLR7/8, and 9 localize in the endosome surface. Activation of two major adaptive downstream proteins, MYS88 and TRIF, leads to production of pro‐inflammatory cytokines and IFN I. Activation of TRIF induces activation of TRAF3, which activates IRF3 and leads to production of IFN I. MYD88 induces activation of TRAF6 in TLR2/6 as well as TLR4 pathway but leads to activation of IRAK4 and indirectly TRAF6 and TRAF3 in TLR7/9 and TLR9 pathway. Activation of NF‐kB signaling through TRAF6 increases production of pro‐inflammatory cytokines and activation of IRF7 leads to production of IFN I. dsRNA, double strand RNA; IFN I, interferon type 1; LPS, lipopolysaccharides; MYD88, myeloid differentiation primary response 88; NF‐kB, nuclear factor k‐light‐chain‐enhancer; ssRNA, single strand RNA; TRAF, tumor necrosis factor receptor‐associated factor; TRIF, TIR‐domain‐containing adapter‐inducing interferon‐β