Abstract
Dengue virus (DENV) is the leading cause of mosquito-borne viral illness and death in humans. Like many viruses, DENV has evolved potent mechanisms that abolish the antiviral response within infected cells. Nevertheless, several in vivo studies have demonstrated a key role of the innate immune response in controlling DENV infection and disease progression. Here, we report that sensing of DENV infected cells by plasmacytoid dendritic cells (pDCs) triggers a robust TLR7-dependent production of IFNα, concomitant with additional antiviral responses, including inflammatory cytokine secretion and pDC maturation. We demonstrate that unlike the efficient cell-free transmission of viral infectivity, pDC activation depends on cell-to-cell contact, a feature observed for various cell types and primary cells infected by DENV, as well as West Nile virus, another member of the Flavivirus genus. We show that the sensing of DENV infected cells by pDCs requires viral envelope protein-dependent secretion and transmission of viral RNA. Consistently with the cell-to-cell sensing-dependent pDC activation, we found that DENV structural components are clustered at the interface between pDCs and infected cells. The actin cytoskeleton is pivotal for both this clustering at the contacts and pDC activation, suggesting that this structural network likely contributes to the transmission of viral components to the pDCs. Due to an evolutionarily conserved suboptimal cleavage of the precursor membrane protein (prM), DENV infected cells release uncleaved prM containing-immature particles, which are deficient for membrane fusion function. We demonstrate that cells releasing immature particles trigger pDC IFN response more potently than cells producing fusion-competent mature virus. Altogether, our results imply that immature particles, as a carrier to endolysosome-localized TLR7 sensor, may contribute to regulate the progression of dengue disease by eliciting a strong innate response.
Highlights
The innate immune system acts as the first line of defense for the sensing of viral infection
We report that sensing of dengue virus (DENV)-infected cells by non-permissive innate immune cells, the plasmacytoid dendritic cells, triggers a cell-contact- and TLR7-dependent activation of a strong antiviral IFN response
To investigate the mechanisms regulating the IFN response against DENV infection, primary human peripheral blood mononuclear cells (PBMCs) from healthy donors were exposed to supernatants containing DENV virions or DENV infected cells
Summary
The innate immune system acts as the first line of defense for the sensing of viral infection This involves rapid recognition of pathogen-associated molecular patterns (PAMPs), including viral nucleic acids, by pattern recognition receptors (PRRs). This recognition results in an antiviral response characterized by the production of type I interferons (IFNs) and expression of IFNstimulated genes (ISGs). The PRR can be cytoplasmic, e.g., retinoic inducible gene-I (RIG-I)-like receptors (RLRs) and NOD-like receptors (NLRs), or endosomal, e.g., Toll-like receptors (TLRs) [1] Depending on their intracellular localization, virus-induced innate immune signaling typically occurs within cells that are either productively infected or that have internalized viral particles [1,2]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
