Abstract
BackgroundThere is an urgent need to understand the key events driving pathogenesis of severe COVID-19 disease, so that precise treatment can be instituted. In this respect NETosis is gaining increased attention in the scientific community, as an important pathological process contributing to mortality. We sought to test if indeed there exists robust evidence of NETosis in multiple transcriptomic data sets from human subjects with severe COVID-19 disease. Gene set enrichment analysis was performed to test for up-regulation of gene set functional in NETosis in the blood of patients with COVID-19 illness.ResultsBlood gene expression functional in NETosis increased with severity of illness, showed negative correlation with blood oxygen saturation, and was validated in the lung of COVID-19 non-survivors. Temporal expression of IL-6 was compared between severe and moderate illness with COVID-19. Unsupervised clustering was performed to reveal co-expression of IL-6 with complement genes. In severe COVID-19 illness, there is transcriptional evidence of activation of NETosis, complement and coagulation cascade, and negative correlation between NETosis and respiratory function (oxygen saturation). An early spike in IL-6 is observed in severe COVID-19 illness that is correlated with complement activation.ConclusionsBased on the transcriptional dynamics of IL-6 expression and its downstream effect on complement activation, we constructed a model that links early spike in IL-6 level with persistent and self-perpetuating complement activation, NETosis, immunothrombosis and respiratory dysfunction. Our model supports the early initiation of anti-IL6 therapy in severe COVID-19 disease before the life-threatening complications of the disease can perpetuate themselves autonomously.
Highlights
There is an urgent need to understand the key events driving pathogenesis of severe COVID-19 disease, so that precise treatment can be instituted
Human transcriptomic data were extracted from published data sets of patients of COVID-19 from different tissues: whole blood [13], peripheral blood mononuclear cells (PBMC) [14], and lung tissue [15]
Whole blood was especially selected because it includes neutrophils that are directly responsible for formation of Neutrophil Extracellular Traps (NET)
Summary
There is an urgent need to understand the key events driving pathogenesis of severe COVID-19 disease, so that precise treatment can be instituted. In this respect NETosis is gaining increased attention in the scientific community, as an important pathological process contributing to mortality. We sought to test if there exists robust evidence of NETosis in multiple transcriptomic data sets from human subjects with severe COVID-19 disease. 19 [8, 9] Such treatment is premised on the induction of intra-pulmonary inflammation by SARS-Cov-2 infection that leads to severe local vascular dysfunction including micro-thrombosis, haemorrhage and pulmonary intravascular coagulopathy [10]. It is important to understand the temporal and/or causal relationship of the cytokine up-regulation with coagulopathy and respiratory dysfunction
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