Biomedical Engineering; Molecular Medicine; Applied Microbiology and Biotechnology; Bioengineering; Biotechnology
Abstract :
[en] Understanding the mechanisms of coronavirus disease 2019 (COVID-19) disease severity to efficiently design therapies for emerging virus variants remains an urgent challenge of the ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules and the host proteome, and the vast majority of these virus–host contacts (the ‘contactome’) have not been identified. Here, we present a systematic contactome map of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the human host encompassing more than 200 binary virus–host and intraviral protein–protein interactions. We find that host proteins genetically associated with comorbidities of severe illness and long COVID are enriched in SARS-CoV-2 targeted network communities. Evaluating contactome-derived hypotheses, we demonstrate that viral NSP14 activates nuclear factor κB (NF-κB)-dependent transcription, even in the presence of cytokine signaling. Moreover, for several tested host proteins, genetic knock-down substantially reduces viral replication. Additionally, we show for USP25 that this effect is phenocopied by the small-molecule inhibitor AZ1. Our results connect viral proteins to human genetic architecture for COVID-19 severity and offer potential therapeutic targets.
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] BAEF - Belgian American Educational Foundation [BE] Télévie [BE]
Funding number :
Fonds de la Recherche Scientifique (FRS-FNRS) grant PER-40003579
Funding text :
We thank P. Charneau for the hACE2 lentivirus. This work was supported by a Canadian Institutes for Health Research Foundation Grant (F.P.R.), the Canada Excellence Research Chairs Program (F.P.R.), the Thistledown Foundation (F.P.R.); the LabEx Integrative Biology of Emerging Infectious Diseases (10-LABX-0062; Y.J., C.D.) and Platform for European Preparedness Against (Re-)emerging Epidemics, EU (602525; Y.J. and C.D.), the European Union’s Horizon 2020 Research and Innovation Programme (Project ID 101003633, RiPCoN; P.F.-B., C.B., P.A.), HDHL-INTIMIC ‘Interrelation of the Intestinal Microbiome, Diet and Health’ (BMBF Project ID 01EA1803; P.F.-B.), the Free State of Bavaria’s AI for Therapy (AI4T) Initiative through the Institute of AI for Drug Discovery (AID) (P.F.-B.) and Fonds de la Recherche Scientifique (FRS-FNRS) grant PER-40003579 (J.-C.T., L.W.). F.L. was supported by a Belgian American Educational Foundation doctoral research fellowship, a Wallonia-Brussels International (WBI)-World Excellence fellowship and Fonds de la Recherche Scientifique (FRS-FNRS)-Télévie grant FC31747 (Crédit n° 7459421F). M.V. is a Chercheur Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium). C.P. was supported by a Ramon y Cajal fellowship (RYC-2017–22959). G.D. was supported by the Ministère de l’Education Nationale, de la Recherche et de l’Innovation with a fellowship from Université Paris Cité.
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