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10.15252/embj.2021109622

http://scihub22266oqcxt.onion/10.15252/embj.2021109622
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35178710!9108609!35178710
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suck abstract from ncbi


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pmid35178710      EMBO+J 2022 ; 41 (10): e109622
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  • TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection #MMPMID35178710
  • van der Sluis RM; Cham LB; Gris-Oliver A; Gammelgaard KR; Pedersen JG; Idorn M; Ahmadov U; Hernandez SS; Cemalovic E; Godsk SH; Thyrsted J; Gunst JD; Nielsen SD; Jorgensen JJ; Bjerg TW; Laustsen A; Reinert LS; Olagnier D; Bak RO; Kjolby M; Holm CK; Tolstrup M; Paludan SR; Kristensen LS; Sogaard OS; Jakobsen MR
  • EMBO J 2022[May]; 41 (10): e109622 PMID35178710show ga
  • 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 IFNalpha 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: IFNalpha and IFNlambda1) 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.
  • |*COVID-19/immunology/pathology[MESH]
  • |*Dendritic Cells/immunology/pathology[MESH]
  • |*Toll-Like Receptor 2/immunology[MESH]
  • |*Toll-Like Receptor 7/immunology[MESH]
  • |Cytokines/metabolism[MESH]
  • |Humans[MESH]
  • |Interferon Type I/immunology[MESH]
  • |Interferon-alpha/immunology[MESH]
  • |Interleukin-6/immunology[MESH]
  • |Neuropilin-1/immunology[MESH]


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