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1.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1442406

ABSTRACT

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Subject(s)
COVID-19/immunology , Interferon-alpha/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism , Base Sequence , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interferon-alpha/blood , Pulmonary Fibrosis/pathology , RNA-Seq , Severity of Illness Index , Transcriptome/genetics , United Kingdom , United States
2.
N Engl J Med ; 384(24): 2349-2351, 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1270700
3.
Science ; 371(6530)2021 02 12.
Article in English | MEDLINE | ID: covidwho-1029076

ABSTRACT

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/metabolism , Antibodies, Viral/chemistry , Antibodies, Viral/metabolism , Antibody Affinity , Antigens, Viral/immunology , Binding Sites, Antibody , COVID-19/virology , Cell Line , Cryoelectron Microscopy , Epitopes , Humans , Membrane Fusion , Mutation , Protein Binding , Protein Conformation , Protein Domains , Receptors, Coronavirus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Single-Domain Antibodies/chemistry , Single-Domain Antibodies/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Replication
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