Abstract
Plasmacytoid dendritic cells (pDCs) are specialized in the production of interferons (IFNs) in response to viral infections. The Flaviviridae family comprises enveloped RNA viruses such as Hepatitis C virus (HCV) and Dengue virus (DENV). Cell-free flaviviridae virions poorly stimulate pDCs to produce IFN. By contrast, cells infected with HCV and DENV potently stimulate pDCs via short-range delivery of viral RNAs, which are either packaged within immature virions or secreted exosomes. We report that cells infected with Yellow fever virus (YFV), the prototypical flavivirus, stimulated pDCs to produce IFNs in a TLR7- and cell contact- dependent manner. Such stimulation was unaffected by the presence of YFV neutralizing antibodies. As reported for DENV, cells producing immature YFV particles were more potent at stimulating pDCs than cells releasing mature virions. Additionally, cells replicating a release-deficient YFV mutant or a YFV subgenomic RNA lacking structural protein-coding sequences participated in pDC stimulation. Thus, viral RNAs produced by YFV-infected cells reach pDCs via at least two mechanisms: within immature particles and as capsid-free RNAs. Our work highlights the ability of pDCs to respond to a variety of viral RNA-laden carriers generated from infected cells.
Highlights
Plasmacytoid dendritic cells are rare immune cells that circulate in the blood where they represent on average 0.4% of the whole peripheral blood mononuclear cells (PBMCs)[1]
We examined whether PBMCs isolated from healthy donors produce IFNs in the presence of cell-free yellow fever virus (YFV) virions
In Plasmacytoid dendritic cells (pDCs)-depleted PBMCs cultured with infected Huh7.5 cells, IFN-α and -III production was significantly reduced compared to total PBMCs (Fig. 1D)
Summary
Plasmacytoid dendritic cells (pDCs) are rare immune cells that circulate in the blood where they represent on average 0.4% of the whole peripheral blood mononuclear cells (PBMCs)[1] They migrate to peripheral lymphoid organs and peripheral tissues upon pathogen infection. Following internalization of circulating cell-free RNA viruses, pDCs are stimulated via recognition of viral ssRNA by the endosomal sensor TLR73. Such sensing of viral nucleic acids occurs mainly independently of viral replication[4,5,6,7]. The IFN response to infected cells by pDCs is of higher magnitude than the one triggered by cell-free viruses and depends on cell-to-cell contacts, TLR7 signaling and viral replication in infected cells but not in pDCs9–12. We investigated these mechanisms using co-culture of YFV-infected hepatoma cells and primary human pDCs
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