Plasmacytoid dendritic cells and Toll-like receptor 7-dependent signalling promote efficient protection of mice against highly virulent influenza A virus

Kaminski, Michael M.; Ohnemus, Annette; Cornitescu, Marius; Staeheli, Peter

doi:10.1099/vir.0.039065-0

Cited by 34 publications

(36 citation statements)

References 31 publications

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“…Similar results were seen with intranasal HSV-1, with TLR2 knockouts impaired in cytokine production but not impaired in survival or viral clearance, while TLR2/9 double knockouts had worse outcomes than did single knockouts (10). In influenza virus infection, TLR7 alone seems to be required for successful clearance of a primary infection (73), but inflammasome signaling through IL-1R is important for protective immunity (74). MyD88 Ϫ/Ϫ mice are far more susceptible to lymphocytic choriomeningitis virus (LCMV) infection, while TLR7/9 double knockouts and IL-1R knockouts show only partial susceptibility (75,76).…”

Section: Discussionsupporting

confidence: 56%

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

Davies

Sei

Siciliano

et al. 2014

J Virol

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Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for TLR2 and its signaling adaptor MyD88 in protective immunity to VACV after intradermal infection. We find that although TLR2 may recognize virus preparations in vitro and have a minor role in preventing dissemination of VACV following systemic infection with large doses of virus, it is wholly disposable in both control of virus replication and induction of adaptive immunity following intradermal infection. In contrast, MyD88 is required for efficient induction of CD4 T cell and B cell responses and for local control of virus replication following intradermal infection. However, even MyD88 is not required to induce local inflammation, inflammatory cytokine production, or recruitment of cells that restrict virus from spreading systemically after peripheral infection. Thus, an effective antiviral response does require MyD88, but TLR2 is not required for control of a peripheral VACV infection. These findings emphasize the importance of studying relevant routes of infection when examining innate sensing mechanisms. IMPORTANCEVaccinia virus (VACV) provides the backbone for some of the most widely used and successful viral vaccine vectors and is also related to the human pathogens Cantagalo virus and molluscum contagiosum virus that infect the skin of patients. Therefore, it is vital to understand the mechanisms that induce a strong innate immune response to the virus following dermal infection. Here, we compare the ability of the innate sensing molecule Toll-like receptor 2 (TLR2) and the signaling molecule MyD88 to influence the innate and adaptive immune response to VACV following systemic or dermal infection.

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Section: Discussionsupporting

confidence: 56%

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

Davies

Sei

Siciliano

et al. 2014

J Virol

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“…However, it should be noted that plasmacytoid dendritic cells (pDCs) are also addressed by both LysM-Cre and CD11c-Cre, although at lower frequency than lung macrophages (32). A recent study suggested that pDCs which appeared to sense virus using TLR7 contribute to IFN production at late stages of infections with influenza virus (17). Thus, it seems likely that at least a fraction of the luciferase activity observed in our LysM/ CD11c-Cre reporter mice originated from pDCs.…”

Section: Cd11cmentioning

confidence: 99%

“…In spite of intensive investigations, surprisingly little is known about the cellular origin of type I IFN in influenza virus-infected lungs. Previous studies demonstrated that various cell types, including macrophages, pneumocytes, and dendritic cells, are able to produce IFN after influenza virus infection (14)(15)(16)(17)(18). However, the relative contributions of these cells to IFN production remained unclear.…”

mentioning

confidence: 99%

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

Kallfass

Lienenklaus

Staeheli

2013

J Virol

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bThe innate host defense against influenza virus is largely dependent on the type I interferon (IFN) system. However, surprisingly little is known about the cellular source of IFN in the infected lung. To clarify this question, we employed a reporter mouse that contains the firefly luciferase gene in place of the IFN-␤-coding region. IFN-␤-producing cells were identified either by simultaneous immunostaining of lungs for luciferase and cellular markers or by generating conditional reporter mice that express luciferase exclusively in defined cell types. Two different strains of influenza A virus were employed that either do or do not code for nonstructural protein 1 (NS1), which strongly suppresses innate immune responses of infected cells. We found that epithelial cells and lung macrophages, which represent the prime host cells for influenza viruses, showed vigorous IFN-␤ responses which, however, were severely reduced and delayed if the infecting virus was able to produce NS1. Interestingly, CD11c؉ cell populations that were either expressing or lacking macrophage markers produced the bulk of IFN-␤ at 48 h after infection with wildtype influenza A virus. Our results demonstrate that the virus-encoded IFN-antagonistic factor NS1 disarms specifically epithelial cells and lung macrophages, which otherwise would serve as main mediators of the early response against infection by influenza virus.

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“…Dual or triple activation of TLR7, TLR8, and/or TLR9 by single-stranded ODNs may, in fact, occur (23). Of interest, plasmacytoid dendritic cells (pDCs) contribute to the protection of the lung against influenza A virus infections, mainly via TLR7 signals (24).…”

mentioning

confidence: 99%

A GpC-Rich Oligonucleotide Acts on Plasmacytoid Dendritic Cells To Promote Immune Suppression

Volpi

Fallarino

Bianchi

et al. 2012

The Journal of Immunology

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Short synthetic oligodeoxynucleotides (ODNs) rich in CpG or GpG motifs have been considered as potential modulators of immunity in clinical settings. In this study, we show that a synthetic GpC-ODN conferred highly suppressive activity on mouse splenic plasmacytoid dendritic cells, demonstrable in vivo in a skin test assay. The underlying mechanism involved signaling by noncanonical NF-κB family members and TGF-β–dependent expression of the immunoregulatory enzyme IDO. Unlike CpG-ODNs, the effects of GpC-ODN required TLR7/TRIF-mediated but not TLR9/MyD88-mediated events, as do sensing of viral ssRNA and the drug imiquimod. Induction of IDO by a GpC-containing ODN could also be demonstrated in human dendritic cells, allowing those cells to assist FOXP3+ T cell generation in vitro. Among potentially therapeutic ODNs, this study identifies GpC-rich sequences as novel activators of TLR7-mediated, IDO-dependent regulatory responses.

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Plasmacytoid dendritic cells and Toll-like receptor 7-dependent signalling promote efficient protection of mice against highly virulent influenza A virus

Cited by 34 publications

References 31 publications

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

A GpC-Rich Oligonucleotide Acts on Plasmacytoid Dendritic Cells To Promote Immune Suppression

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