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1.
Cell ; 184(11): 2955-2972.e25, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1237636

ABSTRACT

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.


Subject(s)
Antibodies, Neutralizing/immunology , HIV-1/immunology , Immunoglobulin Fab Fragments/immunology , Polysaccharides/immunology , SARS-CoV-2/immunology , Simian Immunodeficiency Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , env Gene Products, Human Immunodeficiency Virus/immunology , Animals , B-Lymphocytes/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , Dimerization , Epitopes/immunology , Glycosylation , HIV Antibodies/immunology , HIV Infections/immunology , Humans , Immunoglobulin Fab Fragments/chemistry , Macaca mulatta , Polysaccharides/chemistry , Receptors, Antigen, B-Cell/chemistry , Simian Immunodeficiency Virus/genetics , Vaccines/immunology , env Gene Products, Human Immunodeficiency Virus/chemistry , env Gene Products, Human Immunodeficiency Virus/genetics
2.
Cell ; 182(2): 429-446.e14, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-381993

ABSTRACT

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiratory System/virology , Reverse Genetics/methods , Aged , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Cell Line , Cells, Cultured , Chlorocebus aethiops , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Cystic Fibrosis/pathology , DNA, Recombinant , Female , Furin/metabolism , Humans , Immunization, Passive , Lung/metabolism , Lung/pathology , Lung/virology , Male , Middle Aged , Nasal Mucosa/metabolism , Nasal Mucosa/pathology , Nasal Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Respiratory System/pathology , SARS-CoV-2 , Serine Endopeptidases/metabolism , Vero Cells , Virulence , Virus Replication
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