SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4
Fanny Onodi, Lucie Bonnet‐Madin, Laurent Meertens, Léa Karpf, Justine Poirot, Shen‐Ying Zhang, Capucine Pïcard, Anne Puel, Emmanuelle Jouanguy, Qian Zhang, Jérôme Le Goff, Jean‐Michel Molina, Constance Delaugerre, Jean‐Laurent Casanova, Ali Amara, Vassili Soumelis
Abstract
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.