Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection

Ramlall, Vijendra; Thangaraj, Phyllis; Meydan, Cem; Foox, Jonathan; Butler, Daniel; Kim, Jacob; May, Ben; Freitas, Jessica K De; Glicksberg, Benjamin S.; Mason, Christopher E.; Tatonetti, Nicholas P.; Shapira, Sagi

doi:10.1038/s41591-020-1021-2

Cited by 302 publications

(331 citation statements)

References 33 publications

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“…Similarly, inflammationinduced coagulation pathways, which can themselves be regulated by the complement system, are pivotal in controlling pathogenesis associated with infections. 29 Our RNA work, using nasopharyngeal tissue, extends those findings to show that those pathways are more significantly altered in patients with severe disease outcomes.…”

Section: Discussionsupporting

confidence: 58%

Host transcriptomic profiling of COVID-19 patients with mild, moderate, and severe clinical outcomes

Jain

Ramaswamy

Harilal

et al. 2020

Preprint

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Characterizing key molecular and cellular pathways involved in COVID-19 is essential for disease prognosis and management. We perform shotgun transcriptome sequencing of human RNA obtained from nasopharyngeal swabs of patients with COVID-19, and identify a molecular signature associated with disease severity. Specifically, we identify globally dysregulated immune related pathways, such as cytokine-cytokine receptor signaling, complement and coagulation cascades, JAK-STAT, and TGF-β signaling pathways in all, though to a higher extent in patients with severe symptoms. The excessive release of cytokines and chemokines such as CCL2, CCL22, CXCL9 and CXCL12 and certain interferons and interleukins related genes like IFIH1, IFI44, IFIT1 and IL10 were significantly higher in patients with severe clinical presentation compared to mild and moderate presentations. Moreover, early induction of the TGF-β signaling pathway might be the primary cause of pulmonary fibrosis in patients with severe disease. Differential gene expression analysis identified a small set of regulatory genes that might act as strong predictors of patient outcome. Our data suggest that rapid transcriptome analysis of nasopharyngeal swabs can be a powerful approach to quantify host molecular response and may provide valuable insights into COVID-19 pathophysiology.

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Section: Discussionsupporting

confidence: 58%

Host transcriptomic profiling of COVID-19 patients with mild, moderate, and severe clinical outcomes

Jain

Ramaswamy

Harilal

et al. 2020

Preprint

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“…Recent data from Ramlall et al observed that patients with macular degeneration, one of the most prevalent complement-mediated diseases resulting in enhanced complement activation, were at significantly higher risks for mechanical ventilation and mortality associated with COVID-19 [48]. Toll-like receptor 3 (TLR3) is one of the receptors of innate immunity that recognizes viral genomic RNA or the intermediates during viral replication, including double-stranded RNA (dsRNA).…”

Section: Complement Activation In Covid-19mentioning

confidence: 99%

“…Evolving evidence indicates that extensive crosstalk exists between complement and TLR signaling pathways that may reinforce innate immune response and regulate inflammation [51]. Ramlall et al also noted that none of the (only) four patients with complement deficiency in the whole cohort required ventilation or died after contracting SARS-CoV-2 [48]. Although exceedingly small in number, these findings are hypothesis-generating.…”

Section: Complement Activation In Covid-19mentioning

confidence: 99%

Coagulopathy, endothelial dysfunction, thrombotic microangiopathy and complement activation: potential role of complement system inhibition in COVID-19

Wang

Sahu

Černý

2020

J Thromb Thrombolysis

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Coronavirus disease-2019 (COVID-19) is a rapidly evolving health crisis caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a novel disease entity and we are in a learning phase with regards to the pathogenesis, disease manifestations, and therapeutics. In addition to the primary lung injury, many patients especially the ones with moderate to severe COVID-19 display evidence of endothelial damage, complement activation, which leads to a pro-coagulable state. While there are still missing links in our understanding, the interplay of endothelium, complement system activation, and immune response to the SARS-CoV-2 virus is a surprisingly major factor in COVID-19 pathogenesis. One could envision COVID-19 becoming a novel hematological syndrome. This review is to discuss the available literature with regards to the involvement of the complement system, and coagulation cascade and their interaction with endothelium.

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“…As expected, the core MS1 gene S100A8 was the most significantly up-regulated gene in CD14+ cells generated with severe COVID-19 plasma ( Figure 4h, Supplementary Table 5 ). Among the positively up-regulated genes, we found enriched pathways related to inflammation and coagulation ( Figure 4i ), both of which contribute to the pathogenesis of severe COVID-19 49,50 . Next, we stimulated C1-and C4-treated populations with high molecular weight (HMW) poly-(I:C), a synthetic RNA analogue, or IFN-β, an important mediator of antiviral responses, and observed weaker induction of various cytokines and interferon-stimulated genes in cells generated with C4 plasma in response to poly-(I:C) ( Figure 4j ), whereas no such effect was observed in response to IFN-β.…”

Section: Main Textmentioning

confidence: 99%

Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19

Reyes

Filbin

Bhattacharyya

et al. 2020

Preprint

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A recent estimate suggests that one in five deaths globally are associated with sepsis1. To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity2,3 and our lack of insight into sepsis immunopathology4. These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis5–8. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis or non-infectious critical illness, and validated its expansion in sepsis across thousands of patients using public transcriptomic data9. Despite its marked expansion in the circulation of bacterial sepsis patients, its relevance to viral sepsis and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality and is up-regulated in monocytes from patients with severe COVID-19. We found that blood plasma from bacterial sepsis or COVID-19 patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 and IL-10. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections.

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Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection

Cited by 302 publications

References 33 publications

Host transcriptomic profiling of COVID-19 patients with mild, moderate, and severe clinical outcomes

Host transcriptomic profiling of COVID-19 patients with mild, moderate, and severe clinical outcomes

Coagulopathy, endothelial dysfunction, thrombotic microangiopathy and complement activation: potential role of complement system inhibition in COVID-19

Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19

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