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

Brian Webster (1) , Scott Werneke (2, 3) , Biljana Zafirova (2) , Sebastien This (4) , Séverin Coléon (1) , Elodie Decembre (1) , Helena Païdassi (4) , Isabelle Bouvier (2) , Pierre-Emmanuel Joubert (2) , Darragh Duffy (2) , Thierry Walzer (5) , Matthew Albert (2, 3) , Marlène Dreux (1)

1 Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response
2 Immunobiologie des Cellules dendritiques
3 Genentech, Inc. [San Francisco]
4 Lymphocytes B effecteurs et à mémoire – Effector and memory B cells
5 Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases

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.

Keywords: inflammation; dendritic cells; mouse; immunology; human; interferons; virology

Domains: Life Sciences [q-bio]; Immunology

Brian Webster, Scott Werneke, Biljana Zafirova, Sebastien This, Séverin Coléon, et al.. Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses. eLife, 2018, 7, pp.e34273. ⟨10.7554/eLife.34273⟩. ⟨pasteur-01822838⟩