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1.
EMBO J ; 41(10): e109622, 2022 05 16.
Article in English | MEDLINE | ID: mdl-35178710

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.


Subject(s)
COVID-19 , Dendritic Cells , Toll-Like Receptor 2 , Toll-Like Receptor 7 , 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
2.
Elife ; 102021 09 02.
Article in English | MEDLINE | ID: mdl-34473049

ABSTRACT

Plasmacytoid dendritic cells (pDCs) constitute a rare type of immune cell with multifaceted functions, but their potential use as a cell-based immunotherapy is challenged by the scarce cell numbers that can be extracted from blood. Here, we systematically investigate culture parameters for generating pDCs from hematopoietic stem and progenitor cells (HSPCs). Using optimized conditions combined with implementation of HSPC pre-expansion, we generate an average of 465 million HSPC-derived pDCs (HSPC-pDCs) starting from 100,000 cord blood-derived HSPCs. Furthermore, we demonstrate that such protocol allows HSPC-pDC generation from whole-blood HSPCs, and these cells display a pDC phenotype and function. Using GMP-compliant medium, we observe a remarkable loss of TLR7/9 responses, which is rescued by ascorbic acid supplementation. Ascorbic acid induces transcriptional signatures associated with pDC-specific innate immune pathways, suggesting an undescribed role of ascorbic acid for pDC functionality. This constitutes the first protocol for generating pDCs from whole blood and lays the foundation for investigating HSPC-pDCs for cell-based immunotherapy.


Subject(s)
Ascorbic Acid/pharmacology , Cell Culture Techniques/methods , Cell Differentiation/drug effects , Dendritic Cells , Hematopoietic Stem Cells , Cells, Cultured , Culture Media/chemistry , Dendritic Cells/cytology , Dendritic Cells/drug effects , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Humans , Immunotherapy
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