Differential Expression Patterns of Toll-like Receptors in COVID-19 Patients

Since Toll-like receptors (TLRs) recognize the earliest signs of infection or cell damage, they play fundamental roles in innate immunity. This review summarizes the numerous studies on the expression of TLRs in patients with Coronavirus disease 2019 (COVID-19). We show that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can stimulate at least six of the ten TLRs in humans and that this can shape the severity of COVID-19. Specifically, TLR2, TLR4, and TLR9 appear to play pathogenic roles while TLR3, TLR7, and TLR8 may be protective. Most have mutations that could partly explain the susceptibility phenotypes of COVID-19. Further understanding the roles of TLRs in COVID-19 immunopathogenesis could reveal prognostic biomarkers and help drive the development of novel and effective therapeutics for COVID-19.

Keywords

TLR

COVID-19

SARS-CoV-2

biomarkers

Funding

RS-2023-00217798/National Research Foundation of Korea

2021R1A2C3003675/National Research Foundation of Korea

RS-2023-00242577/National Research Foundation of Korea

2019R1A6C1010020/Korea Basic Science Institute National Research Facilities & Equipment Center

Figures

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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- $\kappa{}$ B activation. TRAF3 causes IRFs to translocate into the nucleus by forming a complex containing TRAF6, IKK $\alpha{}$ , 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- $\beta{}$ ; 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- $\kappa{}$ 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.

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Front. Biosci. (Landmark Ed) Print ISSN 2768-6701 Electronic ISSN 2768-6698