A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis genes' interactions points to Neutrophil extracellular traps as mediators of thrombosis in COVID-19

• Published in: PLoS computational biology 2021-03, Vol.17 (3), p.e1008810
• Main Authors: Ding, Jun, Hostallero, David Earl, El Khili, Mohamed Reda, Fonseca, Gregory Joseph, Milette, Simon, Noorah, Nuzha, Guay-Belzile, Myriam, Spicer, Jonathan, Daneshtalab, Noriko, Sirois, Martin, Tremblay, Karine, Emad, Amin, Rousseau, Simon
• Format: Article
• Language: English
• Subjects: Algorithms; Alveoli; Angiogenesis; Biology and life sciences; Blood clot; Cell Degranulation - genetics; Chronic obstructive pulmonary disease; Complications; Computational Biology; Computer and Information Sciences; Connectivity; Coronaviruses; COVID-19; COVID-19 - complications; COVID-19 - genetics; Development and progression; Diabetes mellitus; Epidemics; Extracellular Traps - genetics; Gene expression; Gene Expression Regulation; Gene Regulatory Networks; Genes; Genetic Predisposition to Disease; Histiocytosis; Humans; Hypertension; Illnesses; Infections; Infertility; Leukocytes (neutrophilic); Lung cancer; Lung diseases; Lungs; Lymphatic diseases; Lymphocytosis; Lymphohistiocytosis, Hemophagocytic - complications; Lymphohistiocytosis, Hemophagocytic - genetics; Medicine and Health Sciences; Methods; Models, Biological; Neutrophils; Obstructive lung disease; Pandemics; Protein Interaction Maps; Proteins; Pulmonary Embolism - etiology; Pulmonary Embolism - genetics; Respiratory distress syndrome; SARS-CoV-2 - genetics; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Swine flu; Thromboembolism; Thrombosis; Thrombosis - etiology; Thrombosis - genetics; Viral diseases; Viral Proteins - genetics
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1008810

Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.