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J Extracell Vesicles ; 10(14): e12173, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544291


Infection with SARS-CoV-2 is associated with thromboinflammation, involving thrombotic and inflammatory responses, in many COVID-19 patients. In addition, immune dysfunction occurs in patients characterised by T cell exhaustion and severe lymphopenia. We investigated the distribution of phosphatidylserine (PS), a marker of dying cells, activated platelets and platelet-derived microparticles (PMP), during the clinical course of COVID-19. We found an unexpectedly high amount of blood cells loaded with PS+ PMPs for weeks after the initial COVID-19 diagnosis. Elevated frequencies of PS+ PMP+ PBMCs correlated strongly with increasing disease severity. As a marker, PS outperformed established laboratory markers for inflammation, leucocyte composition and coagulation, currently used for COVID-19 clinical scoring. PS+ PMPs preferentially bound to CD8+ T cells with gene expression signatures of proliferating effector rather than memory T cells. As PS+ PMPs carried programmed death-ligand 1 (PD-L1), they may affect T cell expansion or function. Our data provide a novel marker for disease severity and show that PS, which can trigger the blood coagulation cascade, the complement system, and inflammation, resides on activated immune cells. Therefore, PS may serve as a beacon to attract thromboinflammatory processes towards lymphocytes and cause immune dysfunction in COVID-19.

COVID-19/blood , Leukocytes, Mononuclear/metabolism , Phosphatidylserines/blood , Adult , Blood Platelets/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/physiopathology , Cell-Derived Microparticles/metabolism , Flow Cytometry , Humans , Platelet Membrane Glycoprotein IIb , Severity of Illness Index , Transcriptome
Science ; 370(6518): 856-860, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-883299


The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.

Betacoronavirus/physiology , Coronavirus Infections/virology , Neuropilin-1/metabolism , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/immunology , Betacoronavirus/genetics , COVID-19 , Caco-2 Cells , Female , HEK293 Cells , Host Microbial Interactions , Humans , Lung/metabolism , Male , Metal Nanoparticles , Mice , Mice, Inbred C57BL , Mutation , Neuropilin-1/chemistry , Neuropilin-1/genetics , Neuropilin-1/immunology , Neuropilin-2/metabolism , Olfactory Mucosa/metabolism , Olfactory Mucosa/virology , Pandemics , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Protein Domains , Respiratory Mucosa/metabolism , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/chemistry