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The innate immune system facilitates defense mechanisms against pathogen invasion and cell damage. Toll-like receptors (TLRs) assist in the activation of the innate immune system by binding to pathogenic ligands. This leads to the generation of intracellular signaling cascades including the biosynthesis of molecular mediators. TLRs on cell membranes are adept at recognizing viral components. Viruses can modulate the innate immune response with the help of proteins and RNAs that downregulate or upregulate the expression of various TLRs. In the case of COVID-19, molecular modulators such as type 1 interferons interfere with signaling pathways in the host cells, leading to an inflammatory response. Coronaviruses are responsible for an enhanced immune signature of inflammatory chemokines and cytokines. TLRs have been employed as therapeutic agents in viral infections as numerous antiviral Food and Drug Administration-approved drugs are TLR agonists.
Sr. No. |
SPs |
PDB ID |
Residues |
Physiological Significance |
Reference |
---|---|---|---|---|---|
1 |
E |
7K3G |
76–109 |
Virus assembly, morphogenesis, viral–host interaction, membrane permeability |
[46] |
2 |
M |
8CTK |
220–260 |
Virus assembly, protein interactions (M–M, M–S, M–N) |
[47] |
3 |
N |
6VY0, 6YUN |
422 |
Abundant RNA-binding protein, virion genome packaging |
[48] |
4 |
S |
6VYB |
1273 |
Main antigen component, triggers the host immune response |
[49] |
Sr. No. |
NSPs |
PDB ID |
Residues |
Physiological Significance |
Reference |
---|---|---|---|---|---|
1 |
NSP1 |
7K3N |
180 |
Protein synthesis, prevents antiviral activity of host cells, degrades host mRNA |
|
2 |
NSP2 |
7MSW |
638 |
Genome replication, disruption of intracellular host signaling |
|
3 |
NSP3 (Papain-like protease, PLpro) |
7KAG, 6WEY, 6WUU, 7LG0 |
1945 |
Integral to viral replication, post-translational processing of the two polyproteins, suppresses host protein synthesis |
|
4 |
NSP4 |
3GZF |
500 |
Protects new replicated virions, replication and assembly of viral structures in host cell |
|
5 |
NSP5 (3C-like protease, 3CLpro) |
6LU7 |
306 |
Protein cleavage capacity (conserved feature) |
|
6 |
NSP6 |
- |
290 |
Induction of autophagosomes, inhibition of viral components to reach host lysosomes |
|
7 |
NSP7 |
7JLT |
83 |
Primase complex (NSP7-NSP8), hetero-oligomeric complex (NSP7-NSP8-RdRp), viral replication |
|
8 |
NSP8 |
7JLT |
198 |
Primase complex (NSP7-NSP8), hetero-oligomeric complex (NSP7-NSP8-RdRp), viral replication |
|
9 |
NSP9 |
6WXD |
113 |
RNA synthesis, carries viral RNA to the host cell, responsible for proliferation |
|
10 |
NSP10 |
6ZPE |
139 |
Cofactor activation for replicative enzymes, complex NSP10-NSP14, viral RNA proofreading |
|
11 |
NSP11 |
- |
13 |
Cleavage product of PP1a by 3CLpro/MPro |
|
12 |
NSP12 (RNA polymerase, RdRp) |
6YYT |
932 |
RNA polymerase activity |
|
13 |
NSP13 |
6JYT |
601 |
Helicase activity |
|
14 |
NSP14 |
7R2V |
527 |
Viral RNA methylation, viral RNA proofreading, methyltransferase activity |
|
15 |
NSP15 |
6WXC |
346 |
Endoribonuclease activity |
|
16 |
NSP16 |
6WVN |
298 |
Viral replication, immune response evasion Viral RNA methylation, methyltransferase activity |
TLRs |
Ligand Recognition |
Form |
Localization |
Adaptor Molecules |
Negative Adaptors |
Response |
Reference |
---|---|---|---|---|---|---|---|
TLR1 |
Triacyl lipopeptides, soluble factors |
Heterodimer |
Cell surface |
MyD88, Mal |
- |
NF-κB activation and proinflammatory cytokines |
|
TLR2 |
Hsp70, lipopeptide, HCV, Nonstructural protein 3 |
Heterodimer |
Cell surface |
MyD88, Mal |
- |
NF-κB activation and proinflammatory cytokines |
|
TLR3 |
dsRNA |
Homodimers |
Endosomal membrane |
TRIF |
SARM negatively regulates TRIF |
IRF activation, production of type 1 IFNs and proinflammatory cytokines |
|
TLR4 |
Lipopolysaccharide, Taxol, S protein of SARS-CoV-2 |
Homodimers |
Cell surface |
MyD88, Mal, TRIF, TRAM |
SARM negatively regulates TRIF and TRAM to consequently reduce inflammation |
Activation of NF-κB, pro-inflammatory cytokines, and IFN-inducible genes |
|
TLR5 |
Flagellin |
Homodimers |
Cell surface |
MyD88 |
- |
Activation of NF-κB and proinflammatory cytokines |
|
TLR6 |
Diacyl lipopeptides, lipoteichoic acid, fungal zymosan |
Heterodimer |
Cell surface |
MyD88, Mal/TIRAP |
- |
Activation of NF-κB and proinflammatory cytokines |
|
TLR7 |
SARS-CoV-2 ssRNA, imadozoquinoline |
Homodimers |
Endosomal membrane |
MyD88 |
- |
IRF activation, production of Type 1 IFNs and proinflammatory cytokines |
|
TLR8 |
SARS-CoV-2 ssRNA |
Endosomal membrane |
MyD88 |
- |
IRF activation, production of type 1 IFNs and proinflammatory cytokines |
||
TLR9 |
Unmethylated CPG-containing ssDNA, hemozoin from the malaria parasite |
Homodimers |
Endosomal membrane |
MyD88 |
- |
IRF activation, production of type 1 IFNs and proinflammatory cytokines |
Drugs |
TLRs |
Viruses |
Significance |
References |
---|---|---|---|---|
Pam2CSK4 |
TLR2 |
Parainfluenza |
Reduced virus replication |
[138] |
INNA-051 |
TLR2 |
SARS-CoV-2 |
Reduces viral RNA load |
[139] |
PIKA |
TLR3 |
Influenza A |
Reduces virus load |
[140] |
Poly ICLC |
TLR3 |
HIV |
Release of IFN-α/β/γ |
[141] |
NA6 |
TLR4 |
Norovirus |
Induction of IFN-β |
[142] |
MPL |
TLR4 |
VZV |
Stimulate cytokines |
[143] |
Flagellin |
TLR5 |
Influenza A |
Reduces virus replication |
[144] |
CBLB502 |
TLR5 |
ConA |
Activation of NF-κB |
[145] |
Pam2CSK4 |
TLR6 |
Parainfluenza |
Reduces virus replication |
[138] |
INNA-051 |
TLR6 |
SARS-CoV-2 |
Reduces viral RNA load |
[139] |
GS-9620 |
TLR7 |
HIV |
Reactivates latency |
[109] |
Vesatolimod |
TLR7 |
HIV |
Modest delay in viral rebound |
[146] |
R848 |
TLR7/8 |
Zika |
Activation of NF-κB |
[147] |
GS-9688 |
TLR8 |
HBV |
Activation of dendritic and natural killer cells |
[148] |
ODN2395 |
TLR9 |
Parainfluenza |
Reduces viral replication |
[138] |
CBLB502—Entolimod; ConA—Concanavalin A; GS-9688—Selgantolimod; R848—Resiquimod; NA6—neoagarohexaose; VZV—Varicella-Zoster virus.