tetano
Editor, Senior Moderator
Nat Biotechnol
. 2022 Oct 10.
doi: 10.1038/s41587-022-01475-z. Online ahead of print.
A proteome-scale map of the SARS-CoV-2-human contactome
Dae-Kyum Kim[SUP] #[/SUP][SUP] 1 2 3 4 5 [/SUP], Benjamin Weller[SUP] #[/SUP][SUP] 6 [/SUP], Chung-Wen Lin[SUP] #[/SUP][SUP] 6 [/SUP], Dayag Sheykhkarimli[SUP] #[/SUP][SUP] 1 2 3 4 [/SUP], Jennifer J Knapp[SUP] #[/SUP][SUP] 1 2 3 4 [/SUP], Guillaume Dugied[SUP] #[/SUP][SUP] 7 8 9 [/SUP], Andreas Zanzoni[SUP] 10 [/SUP], Carles Pons[SUP] 11 [/SUP], Marie J Tofaute[SUP] 12 [/SUP], Sibusiso B Maseko[SUP] 13 [/SUP], Kerstin Spirohn[SUP] 4 14 15 [/SUP], Florent Laval[SUP] 4 13 14 15 16 17 [/SUP], Luke Lambourne[SUP] 4 14 15 [/SUP], Nishka Kishore[SUP] 1 2 3 4 [/SUP], Ashyad Rayhan[SUP] 1 2 3 4 [/SUP], Mayra Sauer[SUP] 6 [/SUP], Veronika Young[SUP] 6 [/SUP], Hridi Halder[SUP] 6 [/SUP], Nora Marín-de la Rosa[SUP] 6 [/SUP], Oxana Pogoutse[SUP] 1 2 3 4 [/SUP], Alexandra Strobel[SUP] 6 [/SUP], Patrick Schwehn[SUP] 6 [/SUP], Roujia Li[SUP] 1 2 3 4 [/SUP], Simin T Rothballer[SUP] 6 [/SUP], Melina Altmann[SUP] 6 [/SUP], Patricia Cassonnet[SUP] 7 8 9 [/SUP], Atina G Coté[SUP] 1 2 3 4 [/SUP], Lena Elorduy Vergara[SUP] 6 [/SUP], Isaiah Hazelwood[SUP] 1 2 3 4 [/SUP], Betty B Liu[SUP] 1 2 3 4 [/SUP], Maria Nguyen[SUP] 1 2 3 4 [/SUP], Ramakrishnan Pandiarajan[SUP] 6 [/SUP], Bushra Dohai[SUP] 6 [/SUP], Patricia A Rodriguez Coloma[SUP] 6 [/SUP], Juline Poirson[SUP] 1 2 18 [/SUP], Paolo Giuliana[SUP] 1 2 3 4 [/SUP], Luc Willems[SUP] 16 17 [/SUP], Mikko Taipale[SUP] 1 2 13 [/SUP], Yves Jacob[SUP] 7 8 9 [/SUP], Tong Hao[SUP] 4 14 15 [/SUP], David E Hill[SUP] 4 14 15 [/SUP], Christine Brun[SUP] 10 19 [/SUP], Jean-Claude Twizere[SUP] 4 13 16 [/SUP], Daniel Krappmann[SUP] 12 [/SUP], Matthias Heinig[SUP] 20 21 [/SUP], Claudia Falter[SUP] 6 [/SUP], Patrick Aloy[SUP] 11 22 [/SUP], Caroline Demeret[SUP] 23 24 25 [/SUP], Marc Vidal[SUP] 26 27 [/SUP], Michael A Calderwood[SUP] 28 29 30 [/SUP], Frederick P Roth[SUP] 31 32 33 34 35 [/SUP], Pascal Falter-Braun[SUP] 36 37 [/SUP]
Affiliations
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.
. 2022 Oct 10.
doi: 10.1038/s41587-022-01475-z. Online ahead of print.
A proteome-scale map of the SARS-CoV-2-human contactome
Dae-Kyum Kim[SUP] #[/SUP][SUP] 1 2 3 4 5 [/SUP], Benjamin Weller[SUP] #[/SUP][SUP] 6 [/SUP], Chung-Wen Lin[SUP] #[/SUP][SUP] 6 [/SUP], Dayag Sheykhkarimli[SUP] #[/SUP][SUP] 1 2 3 4 [/SUP], Jennifer J Knapp[SUP] #[/SUP][SUP] 1 2 3 4 [/SUP], Guillaume Dugied[SUP] #[/SUP][SUP] 7 8 9 [/SUP], Andreas Zanzoni[SUP] 10 [/SUP], Carles Pons[SUP] 11 [/SUP], Marie J Tofaute[SUP] 12 [/SUP], Sibusiso B Maseko[SUP] 13 [/SUP], Kerstin Spirohn[SUP] 4 14 15 [/SUP], Florent Laval[SUP] 4 13 14 15 16 17 [/SUP], Luke Lambourne[SUP] 4 14 15 [/SUP], Nishka Kishore[SUP] 1 2 3 4 [/SUP], Ashyad Rayhan[SUP] 1 2 3 4 [/SUP], Mayra Sauer[SUP] 6 [/SUP], Veronika Young[SUP] 6 [/SUP], Hridi Halder[SUP] 6 [/SUP], Nora Marín-de la Rosa[SUP] 6 [/SUP], Oxana Pogoutse[SUP] 1 2 3 4 [/SUP], Alexandra Strobel[SUP] 6 [/SUP], Patrick Schwehn[SUP] 6 [/SUP], Roujia Li[SUP] 1 2 3 4 [/SUP], Simin T Rothballer[SUP] 6 [/SUP], Melina Altmann[SUP] 6 [/SUP], Patricia Cassonnet[SUP] 7 8 9 [/SUP], Atina G Coté[SUP] 1 2 3 4 [/SUP], Lena Elorduy Vergara[SUP] 6 [/SUP], Isaiah Hazelwood[SUP] 1 2 3 4 [/SUP], Betty B Liu[SUP] 1 2 3 4 [/SUP], Maria Nguyen[SUP] 1 2 3 4 [/SUP], Ramakrishnan Pandiarajan[SUP] 6 [/SUP], Bushra Dohai[SUP] 6 [/SUP], Patricia A Rodriguez Coloma[SUP] 6 [/SUP], Juline Poirson[SUP] 1 2 18 [/SUP], Paolo Giuliana[SUP] 1 2 3 4 [/SUP], Luc Willems[SUP] 16 17 [/SUP], Mikko Taipale[SUP] 1 2 13 [/SUP], Yves Jacob[SUP] 7 8 9 [/SUP], Tong Hao[SUP] 4 14 15 [/SUP], David E Hill[SUP] 4 14 15 [/SUP], Christine Brun[SUP] 10 19 [/SUP], Jean-Claude Twizere[SUP] 4 13 16 [/SUP], Daniel Krappmann[SUP] 12 [/SUP], Matthias Heinig[SUP] 20 21 [/SUP], Claudia Falter[SUP] 6 [/SUP], Patrick Aloy[SUP] 11 22 [/SUP], Caroline Demeret[SUP] 23 24 25 [/SUP], Marc Vidal[SUP] 26 27 [/SUP], Michael A Calderwood[SUP] 28 29 30 [/SUP], Frederick P Roth[SUP] 31 32 33 34 35 [/SUP], Pascal Falter-Braun[SUP] 36 37 [/SUP]
Affiliations
- PMID: 36217029
- DOI: 10.1038/s41587-022-01475-z
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.