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1.
Nat Commun ; 13(1): 868, 2022 02 14.
Article in English | MEDLINE | ID: covidwho-1684025

ABSTRACT

SARS-CoV-2 infection is a major global public health concern with incompletely understood pathogenesis. The SARS-CoV-2 spike (S) glycoprotein comprises a highly conserved free fatty acid binding pocket (FABP) with unknown function and evolutionary selection advantage1,2. Deciphering FABP impact on COVID-19 progression is challenged by the heterogenous nature and large molecular variability of live virus. Here we create synthetic minimal virions (MiniVs) of wild-type and mutant SARS-CoV-2 with precise molecular composition and programmable complexity by bottom-up assembly. MiniV-based systematic assessment of S free fatty acid (FFA) binding reveals that FABP functions as an allosteric regulatory site enabling adaptation of SARS-CoV-2 immunogenicity to inflammation states via binding of pro-inflammatory FFAs. This is achieved by regulation of the S open-to-close equilibrium and the exposure of both, the receptor binding domain (RBD) and the SARS-CoV-2 RGD motif that is responsible for integrin co-receptor engagement. We find that the FDA-approved drugs vitamin K and dexamethasone modulate S-based cell binding in an FABP-like manner. In inflammatory FFA environments, neutralizing immunoglobulins from human convalescent COVID-19 donors lose neutralization activity. Empowered by our MiniV technology, we suggest a conserved mechanism by which SARS-CoV-2 dynamically couples its immunogenicity to the host immune response.


Subject(s)
COVID-19/immunology , Fatty Acids/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Virion/immunology , A549 Cells , Allosteric Site/genetics , Amino Acid Sequence , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Binding Sites/genetics , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Cryoelectron Microscopy/methods , Electron Microscope Tomography/methods , Fatty Acid-Binding Proteins/immunology , Fatty Acid-Binding Proteins/metabolism , Fatty Acids/metabolism , Humans , MCF-7 Cells , Microscopy, Confocal/methods , Protein Binding , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virion/metabolism , Virion/ultrastructure
2.
Front Immunol ; 12: 708149, 2021.
Article in English | MEDLINE | ID: covidwho-1337643

ABSTRACT

Microbial translocation (MT) and intestinal damage (ID) are poorly explored in COVID-19. Aims were to assess whether alteration of gut permeability and cell integrity characterize COVID-19 patients, whether it is more pronounced in severe infections and whether it influences the development of subsequent bloodstream infection (BSI). Furthermore, we looked at the potential predictive role of TM and ID markers on Intensive Care Unit (ICU) admission and in-hospital mortality. Over March-July 2020, 45 COVID-19 patients were enrolled. Markers of MT [LPB (Lipopolysacharide Binding Protein) and EndoCab IgM] and ID [I-FABP (Intestinal Fatty Acid Binding Protein)] were evaluated at COVID-19 diagnosis and after 7 days. As a control group, age- and gender-matched healthy donors (HDs) enrolled during the same study period were included. Median age was 66 (56-71) years. Twenty-one (46.6%) were admitted to ICU and mortality was 22% (10/45). Compared to HD, a high degree of MT and ID was observed. ICU patients had higher levels of MT, but not of ID, than non-ICU ones. Likewise, patients with BSI had lower EndoCab IgM than non-BSI. Interestingly, patients with high degree of MT and low ID were likely to be admitted to ICU (AUC 0.822). Patients with COVID-19 exhibited high level of MT, especially subjects admitted to ICU. COVID-19 is associated with gut permeability.


Subject(s)
COVID-19/metabolism , Intestinal Mucosa/metabolism , SARS-CoV-2/physiology , Acute-Phase Proteins/metabolism , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/mortality , COVID-19/pathology , Carrier Proteins/metabolism , Disease Progression , Fatty Acid-Binding Proteins/metabolism , Female , Humans , Intensive Care Units , Intestinal Mucosa/pathology , Male , Membrane Glycoproteins/metabolism , Middle Aged , Predictive Value of Tests , Prognosis , Survival Analysis , Tight Junctions/metabolism
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