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Cell Rep Med ; 2(1): 100189, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-1065662


The SARS-CoV-2 proteome shares regions of conservation with endemic human coronaviruses (CoVs), but it remains unknown to what extent these may be cross-recognized by the antibody response. Here, we study cross-reactivity using a highly multiplexed peptide assay (PepSeq) to generate an epitope-resolved view of IgG reactivity across all human CoVs in both COVID-19 convalescent and negative donors. PepSeq resolves epitopes across the SARS-CoV-2 Spike and Nucleocapsid proteins that are commonly targeted in convalescent donors, including several sites also recognized in some uninfected controls. By comparing patterns of homologous reactivity between CoVs and using targeted antibody-depletion experiments, we demonstrate that SARS-CoV-2 elicits antibodies that cross-recognize pandemic and endemic CoV antigens at two Spike S2 subunit epitopes. We further show that these cross-reactive antibodies preferentially bind endemic homologs. Our findings highlight sites at which the SARS-CoV-2 response appears to be shaped by previous CoV exposures and which have the potential to raise broadly neutralizing responses.

Molecules ; 25(10)2020 05 22.
Article in English | MEDLINE | ID: covidwho-343433


Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2') cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, and their respective processing proteases, can determine whether the virus can cross species and the level of pathogenicity. Recent comparisons of the genomes of the highly pathogenic SARS-CoV2 and MERS-CoV, with less pathogenic strains (e.g., Bat-RaTG13, the bat homologue of SARS-CoV2) identified possible mutations in the receptor binding domain and in the S1 and S2' cleavage sites of their spike glycoprotein. However, there remains some confusion on the relative roles of the possible serine proteases involved for priming. Using anthrax toxin as a model system, we show that in vivo inhibition of priming by pan-active serine protease inhibitors can be effective at suppressing toxicity. Hence, our studies should encourage further efforts in developing either pan-serine protease inhibitors or inhibitor cocktails to target SARS-CoV2 and potentially ward off future pandemics that could develop because of additional mutations in the S-protein priming sequence in coronaviruses.

Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Serine Proteases/metabolism , Serine Proteinase Inhibitors/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Antigens, Bacterial/toxicity , Antiviral Agents/therapeutic use , Bacterial Toxins/toxicity , Betacoronavirus/pathogenicity , Binding Sites , COVID-19 , Drug Delivery Systems , Female , Furin/pharmacology , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Pandemics , RAW 264.7 Cells , SARS-CoV-2 , Serine Proteinase Inhibitors/therapeutic use , Spike Glycoprotein, Coronavirus/chemistry