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. 2022 Jan 19;14(628):eabj7521.
doi: 10.1126/scitranslmed.abj7521. Epub 2022 Jan 19.

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

Raphael Carapito  1   2   3 Richard Li  4 Julie Helms  1   3   5 Christine Carapito  3   6 Sharvari Gujja  4 Véronique Rolli  1   2   3 Raony Guimaraes  4 Jose Malagon-Lopez  4 Perrine Spinnhirny  1   3 Alexandre Lederle  1   3 Razieh Mohseninia  7 Aurélie Hirschler  3   6 Leslie Muller  3   6 Paul Bastard  8   9   10 Adrian Gervais  9   10 Qian Zhang  8   9   10 François Danion  1   3   11 Yvon Ruch  3   11 Maleka Schenck  3   12 Olivier Collange  3   13 Thiên-Nga Chamaraux-Tran  3   14 Anne Molitor  1   3 Angélique Pichot  1   3 Alice Bernard  1   3 Ouria Tahar  2   3 Sabrina Bibi-Triki  1   3 Haiguo Wu  4 Nicodème Paul  1   3 Sylvain Mayeur  1   3 Annabel Larnicol  1   3 Géraldine Laumond  1   3 Julia Frappier  1   3 Sylvie Schmidt  1   3 Antoine Hanauer  1   3 Cécile Macquin  1   3 Tristan Stemmelen  1   2   3 Michael Simons  15 Xavier Mariette  16   17 Olivier Hermine  10   18 Samira Fafi-Kremer  1   3   19 Bernard Goichot  3   20 Bernard Drenou  21 Khaldoun Kuteifan  22 Julien Pottecher  3   14 Paul-Michel Mertes  3   13 Shweta Kailasan  23 M Javad Aman  23 Elisa Pin  24 Peter Nilsson  24 Anne Thomas  25 Alain Viari  25 Damien Sanlaville  25 Francis Schneider  3   12 Jean Sibilia  1   3   26 Pierre-Louis Tharaux  27 Jean-Laurent Casanova  8   9   10   28 Yves Hansmann  3   11 Daniel Lidar  7   29 Mirjana Radosavljevic  1   2   3 Jeffrey R Gulcher  4 Ferhat Meziani  3   5 Christiane Moog  1   3 Thomas W Chittenden  4   30 Seiamak Bahram  1   2   3
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Free article

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

Raphael Carapito et al. Sci Transl Med. .
Free article

Abstract

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.

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