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Toll-Like Receptors in Antiviral Innate Immunity
Toll-Like Receptors in Antiviral Innate Immunity
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The TLR1 family encompasses TLR1, TLR2, TLR6, and TLR10. These reside on plasma membranes and recognize components of microbial cell walls and membranes such as lipoproteins and peptidoglycans. They function as a heterodimeric receptor, with TLR2 paired with one of the rest of the TLR1 family members. TLR4 and TLR5 also localize to plasma membrane and engage bacterial lipopolysaccharide (LPS) and flagellin, respectively [2]. On the contrary, members of the TLR3, TLR7, and TLR11 families are intracellular TLRs expressed in endosomes and lysosomes. Initially localizing to the endoplasmic reticulum after their synthesis, these TLRs depend on UNC93B1, a polytopic membrane protein for transport to endolysosomal compartments where they are processed by proteases to become functional receptors [11]. TLR3 recognizes double-stranded RNA (dsRNA) [12]. TLR7, TLR8, and TLR9 make up the TLR7 family, with TLR7 and TLR8 detecting single-stranded RNA (ssRNA) while TLR9 engaging unmethylated CpG DNA [2]. In the TLR11 family, TLR11 and TLR12 operate as a heterodimer for sensing profilin from the parasite Toxoplasma gondii [13], while TLR13 detects bacterial 23S ribosomal RNA.
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Furthermore, initiating antiviral immune responses with TLR3 agonists has been shown to provide protection from many different viruses including hepatitis B virus, influenza virus, certain human immunodeficiency virus (HIV) strains, and coronaviruses...
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Of the TLRs characterized to date, several have been linked to antiviral immunity. Among these, TLR3, TLR7, TLR8, and TLR9 detect distinct forms of viral nucleic acids and are critical in the recognition of viral genetic materials in endolysosomal compartments and initiate antiviral responses. TLR2 and TLR4 are two additional TLR family members that have been implicated in the recognition of viral structural and nonstructural proteins leading to inflammatory cytokine production [20], [21], [22], [23]. There is also evidence that TLR13 may recognize viral infection such as that by vesicular stomatitis virus (VSV), although the exact PAMP sensed by TLR13 in this case remains unknown [24]. In this review, we summarize recent advances in the roles of TLRs and their pathways in innate antiviral immunity. We discuss examples of TLR-mediated viral recognition and describe strategies evolved by viruses to circumvent host antiviral innate immune responses triggered by TLRs.
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In response to invading pathogens such as viruses, a powerful antiviral innate immune system is rapidly activated in the host. TLRs are important constituents of this system and recognize a wide variety of PAMPs that are conserved molecular signatures of bacteria and viruses. Of the TLRs that have been identified, six represent a subclass that recognizes viral ligands. TLRs are predominately expressed in immune cells but also found in a variety of cell types. TLR3, TLR7/TLR8, and TLR9 are intracellular receptors located in endosomal compartments in which they detect viral dsRNA, ssRNA, and unmethylated CpG DNA, respectively. TLR2 and TLR4 reside on the cell surface and are stimulated by viral glycoproteins and, in some cases, nonstructural proteins released to extracellular milieu. The signaling mechanisms leading to the induction of antiviral innate immune responses are dependent on the particular TLR activated, its stimulus, and cell type. Through MyD88-dependent and/or TRIF-dependent pathways, TLRs elicit the production of proinflammatory cytokines and/or type I and type III IFNs via activation of the essential transcription factors NF-κB and IRF family members, tailoring the innate immune responses and shaping the subsequent, antigen-specific adaptive immunity. These immune responses often contribute to viral clearance and disease resolution but sometimes can be harmful to the host. In the past decade and a half, much has been learned concerning TLR structures, ligand recognition, signaling mechanisms, and viral countermeasures of TLR signaling, but our knowledge of the precise roles TLRs play in antiviral immunity and viral disease pathogenesis in vivo falls short. Clearly, progresses in these areas using animal infection models that recapitulate viral diseases in humans are urgently needed and will unequivocally help develop novel therapeutic and preventive approaches against viral infections.
Sensing of RNA Viruses: a Review of Innate Immune Receptors Involved in Recognizing RNA Virus Invasion
https://jvi.asm.org/content/86/6/2900
...
... Individual TLRs and the RNA viruses recognized by them:
... https://jvi.asm.org/highwire/markup/62553/expansion
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Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis
Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis
There is substantial evidence that signaling through Toll-like receptor 4 (TLR4) contributes to the pathogenesis of necrotizing enterocolitis (NEC). Pregnane X receptor (PXR), a xenobiotic sensor and signaling intermediate for certain host-bacterial metabolites, has been shown to negatively regulate TLR4 signaling. Here we investigated the relationship between PXR and TLR4 in the developing murine intestine and explored the capacity of PXR to modulate inflammatory pathways involved in experimental NEC.
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We found a reciprocal relationship between the developmental expression of PXR and TLR4 in wild-type murine intestine, with PXR acting to reduce TLR4 expression by decreasing TLR4 mRNA stability. In addition, PXR−/− mice exhibited a remarkably heightened severity of disease in experimental NEC. Moreover, LCA attenuated intestinal proinflammatory responses in the early stages of experimental NEC.
Activation of PXR inhibits LPS-induced NF-κB activation by increasing IκBα expression in HepG2 cells
Activation of PXR inhibits LPS-induced NF-κB activation by increasing IκBα expression in HepG2 cells - Molecular & Cellular Toxicology
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In this study, we found that rifampicin-activated pregnane X receptor (PXR) plays an important role in the suppression of lipopolysaccharide-activated nuclear factor kappa B (NF-κB) activity by increasing the expression of the inhibitor of κBα (IκBα) in HepG2 cells.
Toll-Like Receptors in Antiviral Innate Immunity
...
The TLR1 family encompasses TLR1, TLR2, TLR6, and TLR10. These reside on plasma membranes and recognize components of microbial cell walls and membranes such as lipoproteins and peptidoglycans. They function as a heterodimeric receptor, with TLR2 paired with one of the rest of the TLR1 family members. TLR4 and TLR5 also localize to plasma membrane and engage bacterial lipopolysaccharide (LPS) and flagellin, respectively [2]. On the contrary, members of the TLR3, TLR7, and TLR11 families are intracellular TLRs expressed in endosomes and lysosomes. Initially localizing to the endoplasmic reticulum after their synthesis, these TLRs depend on UNC93B1, a polytopic membrane protein for transport to endolysosomal compartments where they are processed by proteases to become functional receptors [11]. TLR3 recognizes double-stranded RNA (dsRNA) [12]. TLR7, TLR8, and TLR9 make up the TLR7 family, with TLR7 and TLR8 detecting single-stranded RNA (ssRNA) while TLR9 engaging unmethylated CpG DNA [2]. In the TLR11 family, TLR11 and TLR12 operate as a heterodimer for sensing profilin from the parasite Toxoplasma gondii [13], while TLR13 detects bacterial 23S ribosomal RNA.
...
Furthermore, initiating antiviral immune responses with TLR3 agonists has been shown to provide protection from many different viruses including hepatitis B virus, influenza virus, certain human immunodeficiency virus (HIV) strains, and coronaviruses...
...
Of the TLRs characterized to date, several have been linked to antiviral immunity. Among these, TLR3, TLR7, TLR8, and TLR9 detect distinct forms of viral nucleic acids and are critical in the recognition of viral genetic materials in endolysosomal compartments and initiate antiviral responses. TLR2 and TLR4 are two additional TLR family members that have been implicated in the recognition of viral structural and nonstructural proteins leading to inflammatory cytokine production [20], [21], [22], [23]. There is also evidence that TLR13 may recognize viral infection such as that by vesicular stomatitis virus (VSV), although the exact PAMP sensed by TLR13 in this case remains unknown [24]. In this review, we summarize recent advances in the roles of TLRs and their pathways in innate antiviral immunity. We discuss examples of TLR-mediated viral recognition and describe strategies evolved by viruses to circumvent host antiviral innate immune responses triggered by TLRs.
...
In response to invading pathogens such as viruses, a powerful antiviral innate immune system is rapidly activated in the host. TLRs are important constituents of this system and recognize a wide variety of PAMPs that are conserved molecular signatures of bacteria and viruses. Of the TLRs that have been identified, six represent a subclass that recognizes viral ligands. TLRs are predominately expressed in immune cells but also found in a variety of cell types. TLR3, TLR7/TLR8, and TLR9 are intracellular receptors located in endosomal compartments in which they detect viral dsRNA, ssRNA, and unmethylated CpG DNA, respectively. TLR2 and TLR4 reside on the cell surface and are stimulated by viral glycoproteins and, in some cases, nonstructural proteins released to extracellular milieu. The signaling mechanisms leading to the induction of antiviral innate immune responses are dependent on the particular TLR activated, its stimulus, and cell type. Through MyD88-dependent and/or TRIF-dependent pathways, TLRs elicit the production of proinflammatory cytokines and/or type I and type III IFNs via activation of the essential transcription factors NF-κB and IRF family members, tailoring the innate immune responses and shaping the subsequent, antigen-specific adaptive immunity. These immune responses often contribute to viral clearance and disease resolution but sometimes can be harmful to the host. In the past decade and a half, much has been learned concerning TLR structures, ligand recognition, signaling mechanisms, and viral countermeasures of TLR signaling, but our knowledge of the precise roles TLRs play in antiviral immunity and viral disease pathogenesis in vivo falls short. Clearly, progresses in these areas using animal infection models that recapitulate viral diseases in humans are urgently needed and will unequivocally help develop novel therapeutic and preventive approaches against viral infections.
Sensing of RNA Viruses: a Review of Innate Immune Receptors Involved in Recognizing RNA Virus Invasion
https://jvi.asm.org/content/86/6/2900
...
... Individual TLRs and the RNA viruses recognized by them:
... https://jvi.asm.org/highwire/markup/62553/expansion
--------------------
Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis
Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis
There is substantial evidence that signaling through Toll-like receptor 4 (TLR4) contributes to the pathogenesis of necrotizing enterocolitis (NEC). Pregnane X receptor (PXR), a xenobiotic sensor and signaling intermediate for certain host-bacterial metabolites, has been shown to negatively regulate TLR4 signaling. Here we investigated the relationship between PXR and TLR4 in the developing murine intestine and explored the capacity of PXR to modulate inflammatory pathways involved in experimental NEC.
...
We found a reciprocal relationship between the developmental expression of PXR and TLR4 in wild-type murine intestine, with PXR acting to reduce TLR4 expression by decreasing TLR4 mRNA stability. In addition, PXR−/− mice exhibited a remarkably heightened severity of disease in experimental NEC. Moreover, LCA attenuated intestinal proinflammatory responses in the early stages of experimental NEC.
Activation of PXR inhibits LPS-induced NF-κB activation by increasing IκBα expression in HepG2 cells
Activation of PXR inhibits LPS-induced NF-κB activation by increasing IκBα expression in HepG2 cells - Molecular & Cellular Toxicology
...
In this study, we found that rifampicin-activated pregnane X receptor (PXR) plays an important role in the suppression of lipopolysaccharide-activated nuclear factor kappa B (NF-κB) activity by increasing the expression of the inhibitor of κBα (IκBα) in HepG2 cells.