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

Abstract

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.

Severe COVID-19 shares a common neutrophil activation signature with other acute inflammatory states

“…This supports the concept that the pathophysiology of HLH does not only involve T cell, NK cell and macrophage dysregulation but also the hyperactivation of neutrophils. In accordance with our findings, it has recently been demonstrated that neutrophils accumulate in inflamed tissues of HLH and COVID-does not return to a homeostatic level due to an ineffective T cytotoxic response 18,19 . Thus, maintaining the immunogenic stimulus for more cytokine/chemokine secretion, which promotes the sustained neutrophil recruitment and consequent tissue damage.…”

“…To the best of our knowledge, it represents the first attempt to systems characterize the common signaling pathways and molecular networks shared by COVID-19 and HLH. In agreement with the recent observation that neutrophil hyperactivation plays a key role in the severity of COVID-19 [81][82][83][84] and HLH 18,19 , our approach indicates that COVID-19 and HLH have a common transcriptional profile formed predominantly by a group of regulatory molecules related to cytokine/chemotaxis and by a group of effector molecules that are linked to neutrophil hyperactivation and disease severity. These data highlight the dual role of neutrophils in providing essential antimicrobial functions, but also initiating tissue injury caused by immune dysregulation 85,86 .…”

“…Our work expands the efforts of others [87][88][89][90][91] and our group 92 to identify networks and pathways involved in the pathogenesis of severe COVID-19. Our multi-layered transcriptomics approach is in agreement with the computational model developed by Ding et al 18 , which is based on a network-informed analysis of the interaction of SARS-CoV-2 and HLH related genes.…”

“…HLH is marked by aberrant activation of B and T lymphocytes and monocytes/macrophages, coagulopathy, hypotension, and ARDS. Recently, neutrophil hyperactivation has been shown to also play a critical role in HLH development 18,19 . This is in agreement with the observation that the HLH-like phenotype observed in severe COVID-19 patients is due to an innate neutrophilic hyperinflammatory response associated with virus-induced hypercytokinaemia which is dominant in patients with an unfavorable clinical course 17 .…”

Characteristics and Prognostic Value of Pleural Effusion in Secondary Hemophagocytic Lymphohistiocytosis

“…This creation of gaps can result in microvascular leak and pleural effusion [21][22][23] . Moreover, HLH was also described in severely ill patients during the COVID-19 pandemic, presenting with vascular injury resulting from hyperin ammation in the alveoli [24] . In one study, Weaver et al [25] reported that hyperin ammation, rather than hemophagocytosis, appears to be the driving cause of HLH pathology.…”