Characterisation of the blood RNA host response underpinning severity in COVID-19 patients

Abstract

Infection with SARS-CoV-2 has highly variable clinical manifestations, ranging from asymptomatic infection through to life-threatening disease. Host whole blood transcriptomics can offer unique insights into the biological processes underpinning infection and disease, as well as severity. We performed whole blood RNA Sequencing of individuals with varying degrees of COVID-19 severity. We used differential expression analysis and pathway enrichment analysis to explore how the blood transcriptome differs between individuals with mild, moderate, and severe COVID-19, performing pairwise comparisons between groups. Increasing COVID-19 severity was characterised by an abundance of inflammatory immune response genes and pathways, including many related to neutrophils and macrophages, in addition to an upregulation of immunoglobulin genes. Our insights into COVID-19 severity reveal the role of immune dysregulation in the progression to severe disease and highlight the need for further research exploring the interplay between SARS-CoV-2 and the inflammatory immune response.

Hyperactive immature state and differential CXCR2 expression of neutrophils in severe COVID-19

“…Maintenance of neutrophil CXCR2 expression in severe COVID-19 may promote lung trafficking and associated tissue damage and perfusion defects. The role of IL-8/CXCR2 signalling in disease progression is supported by whole blood RNA expression profiling (81) and an independent proteomic study (50), both of which report specific upregulation of the pathway in severe COVID-19. CXCR2 inhibitors may have value as therapeutic agents in severe COVID-19 (82).…”

Pseudotemporal whole blood transcriptional profiling of COVID-19 patients stratified by clinical severity reveals differences in immune responses and possible role of monoamine oxidase B

“…We observed upregulation of neutrophil activation pathways, highest in severe >moderate > mild clinical phenotypes ( Clusters 1 and 3 ). Peripheral neutrophilia is a feature of severe COVID-19 [29] and bulk [1, 30] and single-cell [31] RNAseq studies have associated neutrophil pathways with COVID-19 severity. Neutrophil extracellular traps (NETs), networks of chromatin and bactericidal proteins released by neutrophils in response to pathogens, have been implicated in the pathogenesis of severe COVID-19 disease [32, 33].…”

Is SARS-CoV-2 an oncogenic virus?

“…We analyzed TP53 gene expression in blood from COVID-19 patients stratified by severity as well as healthy controls using the RNAseq data from Jackson et al ( 7 ) and n -Counter (overlapping) data from Gómez-Carballa et al ( 8 ) ( n = 65 and n = 30, respectively). Processing of raw data were carried out as in the original articles.…”

“…For the three studies, severity was determined during the acute phase of the infection. Data normalization was undertaken as in ( 7 ). Wilcoxon test was used to assess statistical significance between groups, and Spearman test for the computation of the correlation indices (r) and P -values.…”

“…In addition, we have also observed that TP53 gene expression is negatively correlated with the length of symptoms until sample collection only in severe patients ( Figure 1 A and 1 B ).

Figure 1 (A) TP53 gene expression in blood samples from COVID-19 patients and healthy controls from the RNAseq dataset ( 7 ) and stratified by WHO severity score (left). Correlation between days of symptoms to sample collection and TP53 expression in the RNAseq dataset (right).

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