Abstract
Parapoxvirus ovis (PPVO) is known for its immunostimulatory capacities and has been successfully used to generate vector vaccines effective especially in non-permissive host species. Murine conventional and plasmacytoid dendritic cells (cDC and pDC) are able to recognize PPVO. The PPVO-sensing receptor on pDC is hitherto unknown. In this study we aimed to define the pattern recognition receptor responsible for the activation of murine pDC by inactivated and replication-competent PPVO. We show that PPVO-induced expression of type I and type III interferons, pro-inflammatory cytokines, and co-stimulatory CD86 by bone marrow-derived pDC but not cDC is blocked by chloroquine, an inhibitor of endosomal maturation. The activation of pDC is independent of viral replication and depends mainly on TLR9. Moreover, the use of phosphatidylinositol 3-kinase inhibitor wortmannin or C-Jun-N-terminal kinase inhibitor SP600125 results in significant reduction of PPVO-induced pDC activation. Taken together, our data identify endosomal TLR9 as PPVO-sensing receptor in pDC.
Highlights
Parapoxvirus ovis (PPVO), known as orf virus, is an enveloped virus with a GC-rich genome [1,2] and the prototype species of the genus parapoxvirus in the Poxviridae family
Endosomal maturation is a prerequisite for PPVOinduced activation of plasmacytoid dendritic cells (pDC), but not of Conventional dendritic cells (cDC)
In a previous study we showed that chemically inactivated PPVO activates conventional dendritic cells in a MyD88- and TRIF-independent manner, whereas the activation of plasmacytoid dendritic cells relies on TLR-related signal adaptor MyD88 [6]. pDC especially express endosomal TLRs
Summary
Parapoxvirus ovis (PPVO), known as orf virus, is an enveloped virus with a GC-rich genome [1,2] and the prototype species of the genus parapoxvirus in the Poxviridae family. PPVO enhances innate immune mechanisms such as phagocytosis, the generation of reactive oxygen intermediates, pro-inflammatory cytokines and especially production of type I interferons (IFN) [4,5,6,7]. The induction of type III IFN in plasmacytoid dendritic cells (pDC) by PPVO has been shown [7]. With its effects on innate immune mechanisms PPVO was shown to interfere with the replication and pathogenesis of other viruses in vivo and in vitro [10]. With its immunomodulatory properties PPVO efficiently primes adaptive immune responses when used as a vaccine vector even in non-permissive host species [11,12,13,14]
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