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

Brian Webster,Pierre-Emmanuel Joubert,Marlène Dreux,Helena Paidassi,Matthew L Albert,Séverin Coléon,Scott W Werneke,Elodie Décembre,Sébastien This,Darragh Duffy,Thierry Walzer,Biljana Zafirova,Isabelle Bouvier

doi:10.7554/elife.34273

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.

Highlights

Upon sensing invading viruses, host cells produce type I interferons (IFNs), leading to the expression of an array of IFN-stimulated genes (ISGs)
We showed that plasmacytoid dendritic cells (pDCs) TNFa levels in response to IMQ were not diminished in presence of dengue virus (DENV)-infected cells (Figure 1—figure supplement 1A)
These results indicated that DENV is neither promoting nor preventing the activation of nuclear factor-kappa B (NF-kB)-induced TNFa production by pDCs

Summary

Introduction

Host cells produce type I interferons (IFNs), leading to the expression of an array of IFN-stimulated genes (ISGs). We and others have recently highlighted the existence of alternative or indirect pathogen-sensing mechanisms that circumvents cell-intrinsic viral evasion mechanisms (Webster et al, 2016) Such alternative pathways involve the sensing of infected target cells by plasmacytoid dendritic cells (pDCs), a DC subtype specialized in the production of robust level of type I IFNs (referred to as IFN-I) (Swiecki and Colonna, 2015). This was illustrated in the context of dengue virus (DENV), a positive-sense single-stranded RNA virus, which represents global health concerns (Bhatt et al, 2013). Recent in vitro work highlighted a newly defined mode of pDC activation, which

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Conclusion