A proteome-scale map of the SARS-CoV-2–human contactome

Abstract

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.

Risk Factors of Severe COVID-19: A Review of Host, Viral and Environmental Factors

“…Human genetic polymorphisms influence healthy aging and longevity [ 1071 , 1072 ], and predisposition for certain comorbidities, such as type I [ 1073 , 1074 ] and II [ 1075 , 1076 ] diabetes mellitus, obesity [ 1077 , 1078 ] and cardiovascular disease [ 1079 , 1080 ]. Several polymorphisms involved in the SARS-CoV-2-human protein contactome have been associated also with non-communicable diseases (cardiovascular diseases, obesity, schizophrenia) [ 1081 ].…”

Repurposing Drugs for the Treatment of COVID-19 and Its Cardiovascular Manifestations

“…One of these drugs, carvedilol, was validated to show clinical benefits for patients with COVID-19 in an electronic health records analysis and antiviral properties in a human lung cell line infected with SARS-CoV-2. Similarly, Kim et al 76 created another proteome-scale map of the SARS-CoV-2–human interactome through which the human genetic architecture for COVID-19 severity was revealed, offering an important data resource for discovering potential therapeutic targets. Although SARS-CoV-2-host interactomes are great resources for understanding viral replication, knowledge of downstream pathways, including all potential viral receptors, host cell proteases, and cofactors, is necessary for the validation of critical host machineries.…”

A computational map of the human-SARS-CoV-2 protein–RNA interactome predicted at single-nucleotide resolution

“…The first group corresponds to RBP-SARS-CoV-2 interactomes established from affinity purification and mass spectrometry ( 18 , 19 , 29 ) and computational predictions in UTRs and Spike viral regions from catRAPIDomics ( 49 ) and PRISMNet ( 50 ). The second group gathers results from viral-host protein–protein interactions (PPIs) measured by affinity-purification followed by mass spectrometry ( 7 , 28 )] and yeast two hybrid screenings ( 51 ). The third group corresponds to functional evidence from multi OMICS data, including the regulation of the host proteomics, phosphoproteomics, ubiquitinomics and transcriptomics up to 24 h after coronavirus infection ( 7 , 52 ), as well as the effectome, which includes deregulated host proteins 72 h after SARS-CoV-2 induced expression of each of the viral proteins ( 7 ).…”