Fig. 1.TLR signaling pathways that are activated by SARS-CoV-2
infection. Six human TLRs demonstrate altered expression in COVID-19 patients.
They function as homodimers (TLR3, TLR4, TLR7, TLR8, and TLR9) or heterodimers
(TLR2/1 and TLR2/6) and are located on the cell surface (TLR2 and TLR4) or within
intracellular compartments (TLR3, TLR4, TLR7, TLR8, and TLR9). The six TLRs are
activated by PAMPs or DAMPs produced by SARS-CoV-2 infection. Their cytosolic
domains then dimerize, which induces the binding of adaptor proteins, including
MyD88 (brown horseshoe shape), MAL/TIRAP (light-pink oval shape), TRIF (yellow
horseshoe shape), and TRAM (purple oval shape). These proteins in turn initiate
downstream signaling pathways which include interactions between IRAK family and
TRAFs. TRAF6 activates TAK1 with its adaptor proteins, TAB2 and TAB3. Activation
of MAPK family members, such as p38 and JNK, are followed. TAK1 also stimulates
the IKK complex and leads to NF-B activation. TRAF3 causes IRFs to
translocate into the nucleus by forming a complex containing TRAF6,
IKK, and other kinases, or by recruiting TBK1 and IKKi. These
downstream signaling pathways result in the secretion of pro-inflammatory
cytokines and/or type-I IFNs. dsRNA, double-stranded RNA; ssRNA, single-stranded
RNA; IFN, interferon; LPS, Lipopolysaccharide; MyD88, Myeloid differentiation
factor 88; MAL, MyD88-adaptor-like protein; TIRAP, TIR-domain containing adaptor
protein; TRAM, TRIF-related adapter molecule; TRIF, TIR-domain-containing
adapter-inducing interferon-; IRAK, Interleukin (IL)-1
receptor-associated kinase; TRAF, TNF receptor-associated factor; TAK1,
Transforming growth factor beta-activated kinase 1; TAB, TAK1-binding protein;
MAPK, mitogen-activated protein kinase; TBK1, Tank-binding kinase 1; IKK,
Inhibitor of NF-B kinase; SARS-CoV-2, severe acute respiratory syndrome
coronavirus-2; COVID-19, Coronavirus disease 2019; TLR, Toll-like receptor;
PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular
patterns; JNK, c-Jun N-terminal Kinase; IRF, interferon regulatory factor; AP,
activator protein; CREB, cAMP response element-binding protein; MKK,
mitogen-activated protein kinase kinase. Created with https://www.biorender.com.