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TLR Signaling

Written/Edited by Julian Pampel, BSc

As part of the innate immune system the Toll-like receptor (TLR) signaling pathway contributes to the first line of defense against microbial pathogens. The innate immune system was historically considered nonspecific in response to different invading pathogens, targeting a wide array of pathogenic organisms, including viruses, bacteria, and fungi. This paradigm substantially shifted with the discovery of the Toll receptor in Drosophila.

To date, 10 members of the family have been identified in human and 13 in mouse. Homologs have also been discovered in plants, illustrating the high-degree of conservation in this receptor class.

Different TLRs recognize specific pathogen-associated molecular patterns (PAMPs). The chemical nature of these PAMPs is highly diverse; e.g. lipopolysaccharide (LPS) of gram-negative bacteria are recognized by TLR4 while TLR5 recognizes the bacterial protein flagellin. Ligands for TLR3, 7, 8, and 9 are nucleic acids, and TLR2 is specific for lipoproteins.

Binding of a TLR ligand to the N-terminal ectodomain of a TLR prompts the formation of TLR homo- or heterodimers. Following dimerization, TLR signals are transduced via a cytoplasmic C-terminal Toll IL-1 receptor (TIR) domain to a set of adapter proteins.

Downstream, TLR signaling engages two distinct pathways in which either TRIF (TICAM2) or MyD88 are the key component. Both pathways culminate in the induction of inflammatory cytokines (TNF, IL-6, IL-12), type I interferons (IFN-alpha, IFN-beta), or apoptosis. Furthermore, TLR signaling induces dendritic cell maturation and contributes consequently to the adaptive immune response.

TLR3 is able to recognize dsDNA and reacts to viral infection. SARS-CoV-2 effectively evades the host response by manipulating the immune answer on several points. Cytokine as well as intererfon signaling ist disturbed.
More information to SARS-CoV-2 Interferon Antagonism and antibodies for key actors and inhibitors.

References

Cook, Pisetsky, Schwartz: "Toll-like receptors in the pathogenesis of human disease." in: Nature immunology, Vol. 5, Issue 10, pp. 975-9, (2004) (PubMed).
Yamamoto, Sato, Hemmi, Hoshino, Kaisho, Sanjo, Takeuchi, Sugiyama, Okabe, Takeda, Akira: "Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway." in: Science (New York, N.Y.), Vol. 301, Issue 5633, pp. 640-3, (2003) (PubMed).
Totura, Whitmore, Agnihothram, Schäfer, Katze, Heise, Baric: "Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection." in: mBio, Vol. 6, Issue 3, pp. e00638-15, (2016) (PubMed).
Totura, Whitmore, Agnihothram, Schäfer, Katze, Heise, Baric: "Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection." in: mBio, Vol. 6, Issue 3, pp. e00638-15, (2016) (PubMed).

Selected TLR Signaling Antibodies & ELISA Kits

Product

Reactivity

Validations

Cat. No.

Quantity

Price

anti-MYD88 antibody (Internal Region)

Reactivity Human

Validations

Cat. No. ABIN185362

Quantity 100 μg

Price $448.50

anti-IL-6 antibody

Reactivity Mouse

Validations

Cat. No. ABIN964780

Quantity 100 μg

Price $537.90

anti-MAP2K3 antibody (AA 1-138)

Reactivity Human

Validations

Cat. No. ABIN5542528

Quantity 0.1 mg

Price $489.50

anti-IRF5 antibody (C-Term)

Reactivity Human

Validations

Cat. No. ABIN184812

Quantity 100 μg

Price $448.50

anti-TICAM1 antibody (C-Term)

Reactivity Human

Validations

Cat. No. ABIN2855929

Quantity 100 μL

Price $609.18

anti-TICAM2 antibody (AA 150-200)

Reactivity Cow, Human, Monkey, Mouse, Opossum, Rat

Validations

Cat. No. ABIN960372

Quantity 100 μg

Price $582.63

Toll-Like Receptors

TLR4 (Toll-Like Receptor 4):

TLR2 (Toll-Like Receptor 2):

TLR2 Antibodies

TLR3 (Toll-Like Receptor 3):

TLR1 (Toll-Like Receptor 1):

TLR5 (Toll-Like Receptor 5):

TLR6 (Toll-Like Receptor 6):

TLR7 (Toll-Like Receptor 7):

TLR8 (Toll-Like Receptor 8):

TLR9 (Toll-Like Receptor 9):

TLR10 (Toll-Like Receptor 10):

Coreceptors

LBP (Lipopolysaccharide Binding Protein):

LY96 (Lymphocyte Antigen 96):

CD36 (CD36):

UNC93B1 (Unc-93 Homolog B1):

UNC93B1 Antibodies

CD14 (CD14):

Adapters

MYD88 (Myeloid Differentiation Primary Response Gene (88)):

TICAM2 (Toll-Like Receptor Adaptor Molecule 2):

TIRAP (Toll-Interleukin 1 Receptor (TIR) Domain Containing Adaptor Protein):

TICAM1 (Toll-Like Receptor Adaptor Molecule 1):

Inhibitors

IRAK3 (Interleukin-1 Receptor-Associated Kinase 3):

SOCS1 (Suppressor of Cytokine Signaling 1):

TNFAIP3 (Tumor Necrosis Factor, alpha-Induced Protein 3):

TAX1BP1 (Tax1 (Human T-Cell Leukemia Virus Type I) Binding Protein 1):

TANK (TRAF Family Member-Associated NFKB Activator):

PTPN1 (Protein tyrosine Phosphatase, Non-Receptor Type 1):

PTPN6 - SHP1:

SARM1 (Sterile alpha and TIR Motif Containing 1):

Transducer

IRAK4 (Interleukin-1 Receptor-Associated Kinase 4):

TRAF3 (TNF Receptor-Associated Factor 3):

TRAF6 (TNF Receptor-Associated Factor 6):

TBK1 (TANK-Binding Kinase 1):

IRAK1 (Interleukin-1 Receptor-Associated Kinase 1):

IRAK2 (Interleukin-1 Receptor-Associated Kinase 2):

IKBKE - IKKi/IKKe:

RIPK1 (Receptor (TNFRSF)-Interacting serine-threonine Kinase 1):

TAB1 (TGF-beta Activated Kinase 1/MAP3K7 Binding Protein 1):

TAB2 (TGF-beta Activated Kinase 1/MAP3K7 Binding Protein 2):

TAB3 (TGF-beta Activated Kinase 1/MAP3K7 Binding Protein 3):

ECSIT (ECSIT):

NF-kappaB

CHUK - IKK alpha:

IKBKB (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase beta):

IKBKG (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase gamma):

NFKB1 (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells 1):

NFkBP65 - NF-kB p65:

NFKBIA (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor, alpha):

Mitogen Activated Protein Kinases

MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1):

MAP3K7 (Mitogen-Activated Protein Kinase Kinase Kinase 7):

MAP2K3 (Mitogen-Activated Protein Kinase Kinase 3):

MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4):

MAP2K6 (Mitogen-Activated Protein Kinase Kinase 6):

MAP2K7 (Mitogen-Activated Protein Kinase Kinase 7):

CREB1 (cAMP Responsive Element Binding Protein 1):

MAPK8 - JNK:

MAPK9 - JNK2:

MAPK10 (Mitogen-Activated Protein Kinase 10):

Interferon Regulatory Factors

IRF7 (Interferon Regulatory Factor 7):

IRF3 (Interferon Regulatory Factor 3):

IRF5 (Interferon Regulatory Factor 5):

Cell Survival

PIK3CA (Phosphoinositide-3-Kinase, Catalytic, alpha Polypeptide):

PIK3CG - PIK3 gamma:

AKT1 (V-Akt Murine Thymoma Viral Oncogene Homolog 1):

AKT2 (V-Akt Murine Thymoma Viral Oncogene Homolog 2):

AKT3 (V-Akt Murine Thymoma Viral Oncogene Homolog 3 (Protein Kinase B, Gamma)):

Apoptosis

FADD (Fas (TNFRSF6)-Associated Via Death Domain):

CASP8 - Caspase 8:

Inflammatory Cytokines and Interferones

TNF alpha (Tumor Necrosis Factor alpha):

IL1B - IL-1 beta:

IL12 (Interleukin 12):

IL8 - IL-8:

IL6 - IL-6:

IFNA (Interferon alpha):

IFNB1 (Interferon, beta 1, Fibroblast):

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