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

2021; American Association for the Advancement of Science; Volume: 14; Issue: 628 Linguagem: Inglês

10.1126/scitranslmed.abj7521

1946-6242

Raphaël Carapito, Richard Y. Li, Julie Helms, Christine Carapito, Sharvari Gujja, Véronique Rolli, Raony Guimaraes, Jose Malagon-Lopez, Perrine Spinnhirny, Alexandre Lederle, Razieh Mohseninia, Aurélie Hirschler, Leslie Muller, Paul Bastard, Adrian Gervais, Qian Zhang, François Danion, Yvon Ruch, Maleka Schenck, Olivier Collange, Thiên‐Nga Chamaraux‐Tran, Anne Molitor, Angélique Pichot, Alice Bernard, Ouria Tahar, Sabrina Bibi-Triki, Haiguo Wu, Nicodème Paul, Sylvain Mayeur, Annabel Larnicol, Géraldine Laumond, Julia Frappier, Sylvie Schmidt, Antoine Hanauer, Cécile Macquin, Tristan Stemmelen, Michael Simons, Xavier Mariette, Olivier Hermine, Samira Fafi‐Kremer, B. Goichot, Bernard Drénou, Khaldoun Kuteifan, Julien Pottecher, Paul‐Michel Mertès, Shweta Kailasan, M. Javad Aman, Elisa Pin, Peter Nilsson, Anne Thomas, Alain Viari, Damien Sanlaville, Francis Schneider, Jean Sibilia, Pierre‐Louis Tharaux, Jean‐Laurent Casanova, Yves Hansmann, Daniel A. Lidar, Mirjana Radosavljevic, Jeffrey R. Gulcher, Ferhat Meziani, Christiane Moog, Thomas W. Chittenden, Seiamak Bahram,

Phagocytosis and Immune Regulation

The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confounding factors such as age and comorbidities, true mediators of this condition have remained elusive. We used a multi-omics analysis combined with artificial intelligence in a young patient cohort where major comorbidities were excluded at the onset. The cohort included 47 “critical” (in the intensive care unit under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cell proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were used. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biology. Among differentially expressed genes, we observed up-regulation of the metalloprotease ADAM9 . This gene signature was validated in a second independent cohort of 81 critical and 73 recovered patients with COVID-19 and was further confirmed at the transcriptional and protein level and by proteolytic activity. Ex vivo ADAM9 inhibition decreased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, cohort of individuals with COVID-19, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. We further identified ADAM9 as a driver of disease severity and a candidate therapeutic target.