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Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands.

Barbalat R, Lau L, Locksley RM, Barton GM - Nat. Immunol. (2009)

Bottom Line: The relevance of this recognition for antiviral immunity remains largely unexplained.TLR2-dependent induction of type I interferon occurred only in response to viral ligands, which indicates that TLR2 is able to discriminate between pathogen classes.Thus, the innate immune system can detect certain non-nucleic acid features of viruses and links this recognition to the induction of specific antiviral genes.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology and Pathogenesis, Department of Molecular & Cell Biology, University of California, Berkeley, California, USA.

ABSTRACT
Despite the paradigm that the innate immune system uses nucleic acid-specific receptors to detect viruses because of a lack of other conserved features, many viruses are recognized by Toll-like receptor 2 (TLR2) and TLR4. The relevance of this recognition for antiviral immunity remains largely unexplained. Here we report that TLR2 activation by viruses led to the production of type I interferon. TLR2-dependent induction of type I interferon occurred only in response to viral ligands, which indicates that TLR2 is able to discriminate between pathogen classes. We demonstrate that this specialized response was mediated by Ly6C(hi) inflammatory monocytes. Thus, the innate immune system can detect certain non-nucleic acid features of viruses and links this recognition to the induction of specific antiviral genes.

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Inflammatory monocytes are required for early production of type I IFN and efficient viral clearance in vivoa) Deletion of inflammatory monocytes in CD11b-DTR mice. Splenocytes were harvested from CD11b-DTR transgenic mice 24 hours after intravenous injection of diptheria toxin or PBS followed by staining with antibodies against Ly6C, CD11b, or Ly6G. b) Inflammatory monocytes are required for production of type I IFN in response to vaccinia virus. CD11b-DTR transgenic mice where injected with diptheria toxin or PBS 24 hours before infection with 1×106 PFU of vaccinia virus. Serum was collected 24 hours post infection and type I IFN were quantified by bioassay. c) Depletion of inflammatory monocytes impairs viral clearance. CD11b-DTR transgenic mice were infected with 1×106 PFU of vaccinia virus 24 hours after intravenous injection of diptheria toxin or PBS. PFU were determined in the liver 48 hours after infection. The data presented are representative of at least 2 experiments.
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Figure 6: Inflammatory monocytes are required for early production of type I IFN and efficient viral clearance in vivoa) Deletion of inflammatory monocytes in CD11b-DTR mice. Splenocytes were harvested from CD11b-DTR transgenic mice 24 hours after intravenous injection of diptheria toxin or PBS followed by staining with antibodies against Ly6C, CD11b, or Ly6G. b) Inflammatory monocytes are required for production of type I IFN in response to vaccinia virus. CD11b-DTR transgenic mice where injected with diptheria toxin or PBS 24 hours before infection with 1×106 PFU of vaccinia virus. Serum was collected 24 hours post infection and type I IFN were quantified by bioassay. c) Depletion of inflammatory monocytes impairs viral clearance. CD11b-DTR transgenic mice were infected with 1×106 PFU of vaccinia virus 24 hours after intravenous injection of diptheria toxin or PBS. PFU were determined in the liver 48 hours after infection. The data presented are representative of at least 2 experiments.

Mentions: Our in vitro analyses of cells from bone marrow and spleen implicate IMs in the recognition of vaccinia virus and suggest that TLR2 activation in these cells leads to production of type I IFN. To address the relevance of these cells during vaccinia virus infection in vivo, we utilized the CD11b-DTR mice described earlier. Although the DTR transgene is driven by the CD11b promoter, previous analyses of these mice have demonstrated that a limited population of CD11b positive cells are efficiently deleted upon injection of diptheria toxin (DT)28. While monocytes and some tissue resident macrophages are removed, other CD11b positive cells (such as neutrophils and activated lymphocytes) remain largely unaffected. Indeed, we observed similar numbers of Ly6G+CD11b+ neutrophils in mice injected with DT or PBS, and the overall profile of CD11b-expressing cells in the spleen remained mostly unchanged (Fig. 6a). In contrast, IMs were deleted quite efficiently, providing a nice system with which to probe the functional relevance of these cells in vivo. Remarkably, when DTR-injected mice were subsequently challenged with vaccinia virus, serum levels of type I IFN were reduced to levels comparable to uninfected mice (Fig. 6b). Injection of DT into non-transgenic mice followed by vaccinia virus infection had no effect on type I IFN production, as expected (Sup. Fig. 5). To assess the relevance of these cells for viral clearance, we determined viral titers in CD11b-DTR mice depleted of IMs prior to infection. Mice lacking IMs displayed higher titers of vaccinia virus in the liver and ovaries (Fig. 6c and Sup. Fig. 6). Collectively, these data indicate that IMs are a key early source of type I IFN during viral infection and are necessary for early restriction of viral replication.


Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands.

Barbalat R, Lau L, Locksley RM, Barton GM - Nat. Immunol. (2009)

Inflammatory monocytes are required for early production of type I IFN and efficient viral clearance in vivoa) Deletion of inflammatory monocytes in CD11b-DTR mice. Splenocytes were harvested from CD11b-DTR transgenic mice 24 hours after intravenous injection of diptheria toxin or PBS followed by staining with antibodies against Ly6C, CD11b, or Ly6G. b) Inflammatory monocytes are required for production of type I IFN in response to vaccinia virus. CD11b-DTR transgenic mice where injected with diptheria toxin or PBS 24 hours before infection with 1×106 PFU of vaccinia virus. Serum was collected 24 hours post infection and type I IFN were quantified by bioassay. c) Depletion of inflammatory monocytes impairs viral clearance. CD11b-DTR transgenic mice were infected with 1×106 PFU of vaccinia virus 24 hours after intravenous injection of diptheria toxin or PBS. PFU were determined in the liver 48 hours after infection. The data presented are representative of at least 2 experiments.
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Figure 6: Inflammatory monocytes are required for early production of type I IFN and efficient viral clearance in vivoa) Deletion of inflammatory monocytes in CD11b-DTR mice. Splenocytes were harvested from CD11b-DTR transgenic mice 24 hours after intravenous injection of diptheria toxin or PBS followed by staining with antibodies against Ly6C, CD11b, or Ly6G. b) Inflammatory monocytes are required for production of type I IFN in response to vaccinia virus. CD11b-DTR transgenic mice where injected with diptheria toxin or PBS 24 hours before infection with 1×106 PFU of vaccinia virus. Serum was collected 24 hours post infection and type I IFN were quantified by bioassay. c) Depletion of inflammatory monocytes impairs viral clearance. CD11b-DTR transgenic mice were infected with 1×106 PFU of vaccinia virus 24 hours after intravenous injection of diptheria toxin or PBS. PFU were determined in the liver 48 hours after infection. The data presented are representative of at least 2 experiments.
Mentions: Our in vitro analyses of cells from bone marrow and spleen implicate IMs in the recognition of vaccinia virus and suggest that TLR2 activation in these cells leads to production of type I IFN. To address the relevance of these cells during vaccinia virus infection in vivo, we utilized the CD11b-DTR mice described earlier. Although the DTR transgene is driven by the CD11b promoter, previous analyses of these mice have demonstrated that a limited population of CD11b positive cells are efficiently deleted upon injection of diptheria toxin (DT)28. While monocytes and some tissue resident macrophages are removed, other CD11b positive cells (such as neutrophils and activated lymphocytes) remain largely unaffected. Indeed, we observed similar numbers of Ly6G+CD11b+ neutrophils in mice injected with DT or PBS, and the overall profile of CD11b-expressing cells in the spleen remained mostly unchanged (Fig. 6a). In contrast, IMs were deleted quite efficiently, providing a nice system with which to probe the functional relevance of these cells in vivo. Remarkably, when DTR-injected mice were subsequently challenged with vaccinia virus, serum levels of type I IFN were reduced to levels comparable to uninfected mice (Fig. 6b). Injection of DT into non-transgenic mice followed by vaccinia virus infection had no effect on type I IFN production, as expected (Sup. Fig. 5). To assess the relevance of these cells for viral clearance, we determined viral titers in CD11b-DTR mice depleted of IMs prior to infection. Mice lacking IMs displayed higher titers of vaccinia virus in the liver and ovaries (Fig. 6c and Sup. Fig. 6). Collectively, these data indicate that IMs are a key early source of type I IFN during viral infection and are necessary for early restriction of viral replication.

Bottom Line: The relevance of this recognition for antiviral immunity remains largely unexplained.TLR2-dependent induction of type I interferon occurred only in response to viral ligands, which indicates that TLR2 is able to discriminate between pathogen classes.Thus, the innate immune system can detect certain non-nucleic acid features of viruses and links this recognition to the induction of specific antiviral genes.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology and Pathogenesis, Department of Molecular & Cell Biology, University of California, Berkeley, California, USA.

ABSTRACT
Despite the paradigm that the innate immune system uses nucleic acid-specific receptors to detect viruses because of a lack of other conserved features, many viruses are recognized by Toll-like receptor 2 (TLR2) and TLR4. The relevance of this recognition for antiviral immunity remains largely unexplained. Here we report that TLR2 activation by viruses led to the production of type I interferon. TLR2-dependent induction of type I interferon occurred only in response to viral ligands, which indicates that TLR2 is able to discriminate between pathogen classes. We demonstrate that this specialized response was mediated by Ly6C(hi) inflammatory monocytes. Thus, the innate immune system can detect certain non-nucleic acid features of viruses and links this recognition to the induction of specific antiviral genes.

Show MeSH
Related in: MedlinePlus