SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4

• Published in: The Journal of experimental medicine Vol. 218; no. 4
• Main Authors: Onodi, Fanny, Bonnet-Madin, Lucie, Meertens, Laurent, Karpf, Léa, Poirot, Justine, Zhang, Shen-Ying, Picard, Capucine, Puel, Anne, Jouanguy, Emmanuelle, Zhang, Qian, Le Goff, Jérôme, Molina, Jean-Michel, Delaugerre, Constance, Casanova, Jean-Laurent, Amara, Ali, Soumelis, Vassili
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05.04.2021
• Subjects: Biomarkers; Brief Definitive Report; Cell Plasticity - immunology; COVID-19 - drug therapy; COVID-19 - immunology; COVID-19 - metabolism; COVID-19 - virology; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - virology; Host-Pathogen Interactions - immunology; Humans; Hydroxychloroquine - pharmacology; Hydroxychloroquine - therapeutic use; Immunomodulation; Immunophenotyping; Infectious Disease and Host Defense; Inflammation Mediators - metabolism; Innate Immunity and Inflammation; Interferon Type I - metabolism; Interferons - metabolism; Interleukin-1 Receptor-Associated Kinases - metabolism; Membrane Transport Proteins - metabolism; SARS-CoV-2 - immunology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20201387

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus–induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2–induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2–induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN–dependent immunity against SARS-CoV-2 infection.