Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort - BAMBOO team Access content directly
Journal Articles Science Translational Medicine Year : 2021

Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort

Raphael Carapito (1, 2, 3, 4, 5) , Richard Li (6) , Julie Helms (1, 2, 3, 5, 7) , Christine Carapito (7, 5) , Sharvari Gujja (6) , Véronique Rolli (1, 2, 3, 4, 5) , Raony Guimaraes (6) , Jose Malagon-Lopez (6) , Perrine Spinnhirny (1, 2, 3, 5) , Alexandre Lederle (1, 2, 3, 5) , Razieh Mohseninia (8) , Aurélie Hirschler (5, 7) , Leslie Muller (5, 7) , Paul Bastard (9, 10, 11) , Adrian Gervais (10, 11) , Qian Zhang (9, 10, 11) , François Danion (1, 2, 3, 5) , Yvon Ruch (5, 12) , Maleka Schenck (5, 12, 13) , Olivier Collange (5, 12, 4) , Thiên-Nga Chamaraux-Tran (5, 14) , Anne Molitor (5, 1, 2, 3) , Angélique Pichot (5, 1, 2, 3) , Alice Bernard (5, 1, 2, 3) , Ouria Tahar (4, 5) , Sabrina Bibi-Triki (5, 1, 2, 3) , Haiguo Wu (6) , Nicodème Paul (5, 1, 2, 3) , Sylvain Mayeur (5, 1, 2, 3) , Annabel Larnicol (5, 1, 2) , Géraldine Laumond (5, 1, 2, 3) , Julia Frappier (5, 1, 2, 3) , Sylvie Schmidt (5, 1, 2, 3) , Antoine Hanauer (5, 1, 2, 3) , Cécile Macquin (5, 1, 2, 3) , Tristan Stemmelen (5, 1, 2, 3, 4) , Michael Simons (14) , Xavier Mariette (15, 16) , Olivier Hermine (11, 17) , Samira Fafi-Kremer (5, 1, 2, 3, 12) , Bernard Goichot (5, 12, 13) , Bernard Drenou (18) , Khaldoun Kuteifan (18) , Julien Pottecher (5, 13) , Paul-Michel Mertes (5, 4) , Shweta Kailasan (19) , M. Javad Aman (19) , Elisa Pin (20) , Peter Nilsson (20) , Anne Thomas (21) , Alain Viari (22, 23) , Damien Sanlaville (21) , Francis Schneider (5, 13) , Jean Sibilia (5, 1, 2, 3, 12) , Pierre-Louis Tharaux (24) , Jean-Laurent Casanova (9, 10, 11) , Yves Hansmann (5, 12) , Daniel Lidar (8) , Mirjana Radosavljevic (5, 1, 2, 3) , Jeffrey Gulcher (6) , Ferhat Meziani (5, 4) , Christiane Moog (5, 1, 2, 3) , Thomas Chittenden (25) , Seiamak Bahram (5, 1, 2, 3, 4)
Anne Thomas
  • Function : Author
Damien Sanlaville

Abstract

The etiopathogenesis of critical COVID-19 remains unknown. Indeed given major confounding factors (age and comorbidities), true drivers of this condition have remained elusive. Here, we employ an unprecedented multi-omics analysis, combined with artificial intelligence, in a young patient cohort where major comorbidities have been excluded at the onset. Here, we established a three-tier cohort of individuals younger than 50 years without major comorbidities. These included 47 “critical” (in the ICU under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) COVID-19 patients as well as 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing and structural causal modeling led to key findings. Critical patients were characterized by exacerbated inflammation, perturbed lymphoid/myeloid compartments, coagulation and viral cell biology. Within a unique gene signature that differentiated critical from non-critical patients, several driver genes promoted critical COVID-19 among which the upregulated metalloprotease ADAM9 was key. This gene signature was supported in a second independent cohort of 81 critical and 73 recovered COVID-19 patients, as were ADAM9 transcripts, soluble form and proteolytic activity. Ex vivo ADAM9 inhibition affected SARS-CoV-2 uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, COVID-19 cohort, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. The key driver, ADAM9, interfered with SARS-CoV-2 biology. A repositioning strategy for anti-ADAM9 therapeutic is feasible.
Fichier principal
Vignette du fichier
Carapito_Version_Acceptee.pdf (1.43 Mo) Télécharger le fichier
Origin Files produced by the author(s)

Dates and versions

hal-03436053 , version 1 (19-11-2021)

Identifiers

Cite

Raphael Carapito, Richard Li, Julie Helms, Christine Carapito, Sharvari Gujja, et al.. Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort. Science Translational Medicine, 2021, pp.1-59. ⟨10.1126/scitranslmed.abj7521⟩. ⟨hal-03436053⟩
289 View
940 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More