Abstract
Infection with the SARS-CoV2 virus can vary from asymptomatic, or flu-like with moderate disease, up to critically severe. Severe disease, termed COVID-19, involves acute respiratory deterioration that is frequently fatal. To understand the highly variable presentation, and identify biomarkers for disease severity, blood RNA from COVID-19 patient in an intensive care unit was analyzed by whole transcriptome RNA sequencing. Both SARS-CoV2 infection and the severity of COVID-19 syndrome were associated with up to 25-fold increased expression of neutrophil-related transcripts, such as neutrophil defensin 1 (DEFA1), and 3-5-fold reductions in T cell related transcripts such as the T cell receptor (TCR). The DEFA1 RNA level detected SARS-CoV2 viremia with 95.5% sensitivity, when viremia was measured by ddPCR of whole blood RNA. Purified CD15+ neutrophils from COVID-19 patients were increased in abundance and showed striking increases in nuclear DNA staining by DAPI. Concurrently, they showed >10-fold higher elastase activity than normal controls, and correcting for their increased abundance, still showed 5-fold higher elastase activity per cell. Despite higher CD15+ neutrophil elastase activity, elastase activity was extremely low in plasma from the same patients. Collectively, the data supports the model that increased neutrophil and decreased T cell activity is associated with increased COVID-19 severity, and suggests that blood DEFA1 RNA levels and neutrophil elastase activity, both involved in neutrophil extracellular traps (NETs), may be informative biomarkers of host immune activity after viral infection.
Highlights
The COVID-19 pandemic, initiated by SARS-CoV2 viral infection, illustrates the need for the rapid detection of novel and variant pathogens, as well as specific risk prediction models to identify patients at high risk of severe or fatal disease
The results indicate that of the 44,783 total transcripts quantified at the gene level, 758 differentially expressed genes (DEGs) were identified between CON and COVIDs (S2 Table)
The decreases in T-cell related transcripts are less striking in magnitude (3–5 fold) than the increased transcripts (20–25 fold), but T-cells (~5% of white blood cell counts (WBC)) are a smaller subset of cells relative to neutrophils (>40% of WBC)
Summary
The COVID-19 pandemic, initiated by SARS-CoV2 viral infection, illustrates the need for the rapid detection of novel and variant pathogens, as well as specific risk prediction models to identify patients at high risk of severe or fatal disease. Clinical risk models for critically ill patients have been only modestly accurate in predicting outcomes for COVID-19 patients [1]. Similar to septic shock, there is an incomplete understanding of the relative contributions of the pathogen load versus a hyperactive immune response by the host. The detection of SARS-CoV2 viral load has mostly been measured only in the accessible regions of the respiratory tract, and requires prior knowledge of the viral sequence to achieve relatively specific PCR amplification. The current studies investigated a complementary strategy that utilizes the host immune system to report a pathogen’s presence and activity. ‘agnostic’ blood biomarkers of infection would have numerous uses, especially in helping to discriminate infectious diseases from aseptic inflammation, such as might occur in asthma, allergies, fibrotic, or autoimmune disorders
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