Toll Like Receptors Proteins


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 Toll Like Receptors Proteins Background

Host cells use various receptors to perceive viral infections by recognizing pathogen-associated molecular patterns (PAMPs) and subsequently induce antiviral responses. Prominent among these receptors are Toll-like receptors (TLRs), which are vertebrate homologues revealed and named after Drosophila Toll receptors. TLRs are critical for innate immune recognition and for inducing immune responses to most microorganism-caused infections. The progress of mammalian genome projects indicates that each mammalian species has approximately 10 TLRs, which are functional for detection of a multitude of molecular ligands derived from various microorganisms as “danger signals” of infections. Six of these TLRs have been implicated in response to viral infection through sensing viral components. Among them, TLR2 and TLR4 hinged on cell cytoplasmic membranes were found to recognize several viral proteins; and especially the functional group of TLR3, TLR7, TLR8 and TLR9 was characterized to sense viral nucleic acid, either virus-derived RNA or DNA molecules. Accordingly, these nucleic acid-sensing TLRs are responsive mainly in acidified intracellular compartments including late endosomes and lysosomes, where most viruses undergo a de-coating process during infection. All TLRs belong to a family of class I transmembrane receptors. Each TLR consists of an extracellular domain (ectodomain) to form a ligand-binding structure, a membrane-spanning α-helix to hinge on the membrane, and a cytoplasmic Toll-interleukin receptor (TIR) domain to transduce postreceptor signaling via interaction with cytoplasmic adaptor proteins.

 

TLR2 and TLR4

Prominently implicated in perceiving ligands derived from bacteria, fungi and stressed host cells, TLR2 and TLR4 also have been demonstrated to mediate antiviral responses via detection of viral proteins. In the reports, hemagglutinin (H) protein of wild-type measles virus induced the production of proinflammatory cytokines such as interleukin-6 (IL-6) in a TLR2-dependent manner in both human and murine monocytes. It was shown that wild-type H protein did not induce IL-6 release in macrophages from TLR2- deficient mice, and mutation of a single amino acid (asparagine at position 481 to tyrosine) of wild-type H protein abolished its ability to activate TLR2. Infection by lymphocytic choriomeningitis virus (LCMV) was recently demonstrated to induce the production of chemokines, such as MCP-1, RANTES and TNF-α in a similar TLR2-dependent manner in glial cells of the central nervous system (CNS). In this case, mice deficient in TLR2 or its downstream adaptor proteins (MyD88 and Mal described late) did not produce any of these chemokines upon LCMV infection; however, LCMV induced a similar chemokine response in both TLR3 and TLR4 knockout glial cells.

On the other hand, TLR4 was found to detect viral fusion protein and to mediate innate immune responses to human respiratory syncytial virus (RSV). TLR4 is also capable of detecting envelope proteins of retroviruses including mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) and, thereby, mediating murine B-cell or dendritic cell activation. One notable phenomenon is that activation of TLR2/4-dependent signals by viral proteins not only induces immune protection in host cells but also may be exploited by viruses to augment infection through upregulating viral receptors on infected cells, which were indicated in interactions of TLR2-measles virus and TLR4-MMTV.

 

TLR3

As a set of universal viral PMAPs, double stranded (ds)-RNA is produced either as an intermediate of viral replication or as part of the viral RNA genome. TLR3 was the first TLR implicated in antiviral responses. Besides its high preference for recognition of synthetic RNA analogs (e.g. polyinosinic acidcytidylic acid (poly(I:C) and especially Ampligen [poly(I)-poly(C12U)]), TLR3 recognizes viral dsRNAs derived from dsRNA viruses (such as reovirus), ssRNA viruses (such as West Nile virus, respiratory syncytial virus, hepatitis C virus and encephalomyocarditis virus) or DNA viruses (such as herpes simplex virus). Whereas there is no doubt about TLR3 recognition of dsRNA, the immune protective role of TLR3 in viral infection is controversial and dependent on different virus-host cell interactions.

TLR3 is expressed in the respiratory tract, and its expression is markedly upregulated in epithelial cells by infection of either influenza A virus or respiratory syncytial virus (RSV). In wild-type mice, pulmonary upregulation of TLR3 post influenza A infection caused acute pneumonia, whereas TLR3-decifient mice developed less severe pneumonia and had an unexpected survival advantage despite higher viral titer in lungs of TLR3-decifient mice. Thus, murine TLR3 signaling contributes to pulmonary clearance of influenza A virus but meanwhile results in detrimental inflammation. In contrast, TLR3 signaling is necessary to maintain proper immune protection in RSV infection because TLR3-deficient mice accumulate much higher T helper 2 cytokines resulting in mucus overproduction in lungs, a pathological feature of RSV infection. TLR3 has been shown to be expressed in glial and neuronal cells and proposed to be involved in intrinsic antiviral mechanisms in the central nervous system. During infection with influenza A virus, TLR3 showed a protective role of ameliorating influenza A virus-induced encephalopathy, as symptoms are profoundly developed in the patients with a missense mutation of the TLR3 protein.

 

TLR7, TLR8 and TLR9

TLR7, 8 and 9 belong to the same functional subfamily based on similarities in their genomic sequences, cellular locations and interacted agonists. TLR7 and 8 are closely related and colocalized on X chromosomes in some mammalian species including humans, pigs and cattle, which have both functional TLR7 and 8. TLR7 and 9 are mainly expressed in pDCs, neutrophils and eosinophils; in contrast, TLR8 mRNA is highly expressed in cDCs, monocytes and macrophages. Before the identification of viral ligands, murine TLR7 and human TLR7 and TLR8 were found to recognize imidazoquinoline compounds, such as imiquimod (R837) and resiquimod (R848), and guanosine analogs such as loxoribine, which have potent antiviral and/or anti-tumor activities. Recent evidence showed that human and murine TLR7 mediates pDC responses to ssRNA viruses including HIV, vesicular stomatitis virus (VSV), Sendai virus and influenza virus and to genomic ssRNA purified from influenza virions. TLR7 engaging activity by these viral ssRNA has been reproduced with synthetic ssRNA oligonucleotides mimicking guanosine (G)/uridine (U) repeats in viral genomes. These U or GU repeats derived from viral RNA genomes were also extensively analyzed as agonists for human TLR8 in PMBCs. In contrast, TLR9 in pDCs detects unmethylated CpG motifs in DNA viruses such as adenovirus, HSV-1 and -2 or murine cytomegalovirus (MCMV). The CpG-containing DNA of HSV-2 engages TLR9 signaling to induce IFN-α production in murine pDCs. TLR9-deficient mice lose resistance to MCMV infection, suggesting that TLR9 signaling is responsible for antiviral responses by sensing the CpG-containing DNA of DNA viruses.