Enhanced TLR7-dependent production of type I interferon by pDCs underlies pandemic chilblains
Outbreaks of chilblains were reported during the COVID-19 pandemic. Given the essential role of type I interferon (I-IFN) in protective immunity against SARS-CoV-2 and the association of chilblains with inherited type I interferonopathies, we hypothesized that excessive I-IFN responses to SARS-CoV-2 might underlie the occurrence of chilblains in this context. We identified a transient I-IFN signature in chilblain lesions, accompanied by an acral infiltration of activated plasmacytoid dendritic cells (pDCs). Patients with chilblains were otherwise asymptomatic or had mild disease without seroconversion. Their leukocytes produced abnormally high levels of I-IFN upon TLR7 stimulation with agonists or ssRNA viruses-particularly SARS-CoV-2-but not with DNA agonists of TLR9 or the dsDNA virus HSV-1. Moreover, the patients' pDCs displayed cell-intrinsic hyperresponsiveness to TLR7 stimulation regardless of TLR7 levels. Inherited TLR7 or I-IFN deficiency confers a predisposition to life-threatening COVID-19. Conversely, our findings suggest that enhanced TLR7 activity in predisposed individuals could confer innate, pDC-mediated, sterilizing immunity to SARS-CoV-2 infection, with I-IFN-driven chilblains as a trade-off.
Authors
- Raphael Jenelten (ORCID: https://orcid.org/0000-0002-0122-8918)
- Ana Joncic
- Charles M. Rice (ORCID: https://orcid.org/0000-0003-3087-8079)
- Marie‐Anne Morren (ORCID: https://orcid.org/0000-0002-4860-5194)
- Darragh Duffy (ORCID: https://orcid.org/0000-0002-8875-2308)
- Danyel Lee (ORCID: https://orcid.org/0000-0003-3124-0245)
- Ahmad Yatim (ORCID: https://orcid.org/0000-0002-4859-4085)
- Jean‐Laurent Casanova (ORCID: https://orcid.org/0000-0002-7782-4169)
- Corentin Le Floc’h (ORCID: https://orcid.org/0009-0007-0590-0437)
- Curdin Conrad (ORCID: https://orcid.org/0000-0002-2547-3440)
- Emmanuelle Jouanguy (ORCID: https://orcid.org/0000-0002-7358-9157)
- Jérémie Le Pen (ORCID: https://orcid.org/0000-0001-7025-9526)
- Michel Gilliet (ORCID: https://orcid.org/0000-0002-4609-3762)
- Vincent Bondet (ORCID: https://orcid.org/0000-0002-6534-0984)
- Jérémy Di Domizio (ORCID: https://orcid.org/0000-0002-6281-3918)
- Shen‐Ying Zhang (ORCID: https://orcid.org/0000-0002-9449-3672)
- Vivien Béziat (ORCID: https://orcid.org/0000-0002-4020-824X)
- Jacques Fellay (ORCID: https://orcid.org/0000-0002-8240-939X)
- Fanny Saidoune (ORCID: https://orcid.org/0009-0002-9776-6370)
Institutions
- Howard Hughes Medical Institute (US)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- Great Ormond Street Hospital (GB)
- Hospital for Sick Children (CA)
- SickKids Foundation (CA)
- Institut des Maladies Génétiques Imagine (FR)
- University College London (GB)
- École Polytechnique Fédérale de Lausanne (CH)
- Rockefeller University (US)
- University of Lausanne (CH)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1084/jem.20231467
- Citations
- 7
- Primary Topic
- Dermatological and COVID-19 studies
- Type
- article
- Field-Weighted Citation Impact
- 14.03
Funders
- National Science Foundation
- Cancer Research Institute
- Fisher Center for Alzheimer's Research Foundation
- Schlumberger Foundation
- St. Giles Foundation
- George Mason University
- Fondation du Souffle
- Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation
- European Commission
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fondation pour la Recherche Médicale
- Institut National Du Cancer
- Fondation Leenaards
- Centre Hospitalier Universitaire Vaudois
- Université Paris-Saclay
- European Academy of Dermatology and Venereology
- European Society for Immunodeficiencies
- National Institutes of Health
- National Cancer Institute
- National Center for Advancing Translational Sciences