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1.
researchsquare; 2023.
Preprint Dans Anglais | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-2501398.v1

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The emergence of new viral threats, wide applications of viruses in biotechnology and challenges associated with viral contamination necessitate multiple types of virustatic agents. Here, we show that highly biocompatible tapered CuS nanoparticles efficiently agglutinate COVID virus with binding affinity dependent on chirality of surface ligands and particle shape. L-penicillamine-stabilized nanoparticles with left-handed curved apexes display half-maximal inhibitory concentration as low as 0.57 pM for authentic SARS-CoV-2 viruses, which is ca 15 times greater than for antibodies. Exposure to elevated temperatures causes no change in activity or biocompatibility of nanoparticles while completely deactivating antibodies. Testing with mice indicates that the chirality-optimized nanoparticles can serve as analogs of high antiviral molecular weight biologics complementing the current spectrum of virustatic agents. Their thermal and chemical stability simplifies their applications in biomedical and biotechnological processes.

2.
biorxiv; 2022.
Preprint Dans Anglais | bioRxiv | ID: ppzbmed-10.1101.2022.11.29.518257

Résumé

Endoplasmic reticulum (ER) aminopeptidase associated with antigen processing (ERAAP) trims peptide precursors in the ER for presentation by major histocompatibility (MHC)-I molecules to surveying CD8+T-cells. This function allows ERAAP to regulate the nature and quality of the peptide repertoire and, accordingly, the resulting immune responses. We recently showed that infection with murine cytomegalovirus leads to a dramatic loss of ERAAP levels in infected cells. In mice, this loss is associated with the activation of QFL T-cells, a subset of T-cells that monitor ERAAP integrity and eliminate cells experiencing ERAAP dysfunction. In this study, we aimed to identify host factors that regulate ERAAP expression level and determine whether these could be manipulated during viral infections. We performed a CRISPR knockout screen and identified ERp44 as a factor promoting ERAAP retention in the ER. ERp44's interaction with ERAAP is dependent on the pH gradient between the ER and Golgi. We hypothesized that viruses that disrupt the pH of the secretory pathway interfere with ERAAP retention. Here, we demonstrate that expression of the Envelope (E) protein from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) leads to Golgi pH neutralization and consequently decrease of ERAAP intracellular levels. Furthermore, SARS-CoV-2-induced ERAAP loss correlates with its release into the extracellular environment. ERAAP's reliance on ERp44 and a functioning ER/Golgi pH gradient for proper localization and function led us to propose that ERAAP serves as a sensor of disturbances in the secretory pathway during infection and disease.


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Syndrome respiratoire aigu sévère , Chromosome Philadelphie
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