Article ; Online: TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection.
2022 Volume 41, Issue 10, Page(s) e109622
Abstract: 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 ( ... ...
| Abstract | 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. |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MeSH term(s) | COVID-19/immunology ; COVID-19/pathology ; Cytokines/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/pathology ; Humans ; Interferon Type I/immunology ; Interferon-alpha/immunology ; Interleukin-6/immunology ; Neuropilin-1/immunology ; SARS-CoV-2 ; Toll-Like Receptor 2/immunology ; Toll-Like Receptor 7/immunology | ||||||||||
| Chemical Substances | Cytokines ; Interferon Type I ; Interferon-alpha ; Interleukin-6 ; TLR2 protein, human ; TLR7 protein, human ; Toll-Like Receptor 2 ; Toll-Like Receptor 7 ; Neuropilin-1 (144713-63-3) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2022-03-01 | ||||||||||
| Publishing country | England | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 586044-1 | ||||||||||
| ISSN | 1460-2075 ; 0261-4189 | ||||||||||
| ISSN (online) | 1460-2075 | ||||||||||
| ISSN | 0261-4189 | ||||||||||
| DOI | 10.15252/embj.2021109622 | ||||||||||
| Shelf mark |
|
||||||||||
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
Full text online
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 1808: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
|||
| Zs.MG 100: Show issues |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.