A multi-omics analysis combined with artificial intelligence was conducted on a cohort of young patients (younger than 50 years) without major comorbidities including 47 “critical” (in the ICU under mechanical ventilation), 25 “non-critical” (in a non-critical care ward) COVID-19 patients and 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.

Carapito R, Li R, Helms J, Carapito C, Gujja S, Rolli V, Guimaraes R, Malagon-Lopez J, Spinnhirny P, Lederle A, Mohseninia R, Hirschler A, Muller L, Bastard P, Gervais A, Zhang Q, Danion F, Ruch Y, Schenck M, Collange O, Chamaraux-Tran TN, Molitor A, Pichot A, Bernard A, Tahar O, Bibi-Triki S, Wu H, Paul N, Mayeur S, Larnicol A, Laumond G, Frappier J, Schmidt S, Hanauer A, Macquin C, Stemmelen T, Simons M, Mariette X, Hermine O, Fafi-Kremer S, Goichot B, Drenou B, Kuteifan K, Pottecher J, Mertes PM, Kailasan S, Aman MJ, Pin E, Nilsson P, Thomas A, Viari A, Sanlaville D, Schneider F, Sibilia J, Tharaux PL, Casanova JL, Hansmann Y, Lidar D, Radosavljevic M, Gulcher JR, Meziani F, Moog C, Chittenden TW, Bahram S. “Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort”. Sci Transl Med. 2021 Oct 26:eabj7521. Epub ahead of print. PMID: 34698500. https://doi.org/10.1126/scitranslmed.abj7521