Portal de Periódicos da CAPES

TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS‐CoV‐2 infection

2022; Springer Nature; Volume: 41; Issue: 10 Linguagem: Inglês

10.15252/embj.2021109622

1460-2075

Renée M. van der Sluis, Lamin B. Cham, Albert Gris‐Oliver, Kristine Raaby Gammelgaard, Jesper G. Pedersen, Manja Idorn, Ulvi Ahmadov, Sabina Sánchez-Hernández, Ena Cémalovic, Stine H. Godsk, Jacob Thyrsted, Jesper Damsgaard Gunst, Silke D Nielsen, Janni J. Jørgensen, Tobias Wang Bjerg, Anders Laustsen, Line S. Reinert, David Olagnier, Rasmus O. Bak, Mads Kjølby, Christian K. Holm, Martin Tolstrup, Søren R. Paludan, Lasse S. Kristensen, Ole S. Søgaard, Kristine Raaby Jakobsen,

Viral Infections and Outbreaks Research

Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL-6. Using an in vitro stem cell-based human pDC model, we further demonstrate that pDCs, while not supporting SARS-CoV-2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines that protect epithelial cells from de novo SARS-CoV-2 infection. Via targeted deletion of virus-recognition innate immune pathways, we identify TLR7-MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll-like receptor (TLR)2 is responsible for the inflammatory IL-6 response. We further show that SARS-CoV-2 engages the receptor neuropilin-1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL-6 response, suggesting neuropilin-1 as potential therapeutic target for stimulation of TLR7-mediated antiviral protection.