Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses

Abstract

Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulatory functions, we developed a mouse model in which IRF7 signaling is restricted to pDC. Despite undetectable levels of IFN-I protein, pDC-restricted IRF7 signaling controlled both viruses and was sufficient to protect mice from lethal CHIKV infection. Early pDC IRF7-signaling resulted in amplification of downstream antiviral responses, including an accelerated natural killer (NK) cell-mediated type II IFN response. These studies revealed the dominant, yet indirect role of pDC IRF7-signaling in directing both type I and II IFN responses during arbovirus infections.

Antiviral Response by Plasmacytoid Dendritic Cells via Interferogenic Synapse with Infected Cells

“…The requirement of interferogenic synapse for a robust IFN response by pDCs thus implies that this antiviral response is confined to the proximity of infected cells. This is reminiscent of previous reports showing a pivotal in vivo antiviral regulation by early pDC response, despite undetectable or very transient/limited pDC-derived type I IFNs at systemic levels (Swiecki et al, 2010;Webster et al, 2018), thus positioning pDC type I IFN secretion as a response likely confined to the infected site. Therefore, the cell contact-dependent robust pDC response could have evolved in favor of the host fitness to locally respond at the infected sites, and thereby to thwart the otherwise harmful systemic IFN and inflammatory responses.…”

“…the surface envelope proteins) accumulate at the cell contact between infected cells and pDCs . The cell-cell contact is increasingly recognized as a requirement for pDC-mediated antiviral state triggered by genetically distant RNA viruses (e.g., Flaviviridae, Picornaviridae, Arenaviridae, Retroviridae, Togaviridae) and in different species (e.g., human, mouse, pig) (Bruni et al, 2015;Decembre et al, 2014;Dreux et al, 2012;Feng et al, 2014;Garcia-Nicolas et al, 2016;Lepelley et al, 2011;Takahashi et al, 2010;Webster et al, 2016;Webster et al, 2018;Wieland et al, 2014), nonetheless how the cell-cell contact mediates pDC response is still largely unknown.…”

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

“…Stimulation of fresh isolated CD14 + monocytes from healthy donors results in differentiation into monocyte-derived dendritic cells (Mo-DCs) after six days of IL-4 and GM-CSF (Supporting Information Fig. 1A), as described [21,22]. At 48 h after infection by DENV-2, up to 28.9% of Mo-DCs were infected (Supporting Information Fig.…”

Toll-Like Receptor 7 (TLR-7) and TLR-9 Agonists Improve Hepatitis C Virus Replication and Infectivity Inhibition by Plasmacytoid Dendritic Cells

“…pDCs in response to TLR stimulation not only produced IFN-␣ but also up to 19 type I IFN subtypes and multiple other cytokines (15,29). However, it has been documented that direct stimulation by RNA viruses such as HCV, dengue virus, and chikungunya virus does not trigger the NF-B pathway in pDCs (30,31). This pathway is responsible for the production of IL-6 and TNF-␣ cytokines and of the expression of CD80 and CD86 (32).…”