# Megakaryocyte phenotyping in response to SARS-CoV-2 variants

## TL;DR

This study shows that different SARS-CoV-2 variants cause similar megakaryocyte activation but distinct gene changes, with elevated IL-8 linked to worse outcomes in COVID-19 patients.

## Contribution

The study reveals distinct transcriptomic effects of SARS-CoV-2 variants on megakaryocytes and identifies IL-8 as a potential biomarker for thrombotic events in COVID-19.

## Key findings

- SARS-CoV-2 variants caused similar megakaryocyte activation but distinct gene expression changes.
- Elevated IL-8 levels were observed in both infected megakaryocytes and plasma of severe COVID-19 patients.
- Higher plasma IL-8 levels were associated with thrombotic events or death in hospitalized patients.

## Abstract

SARS-CoV-2 infection is associated with platelet hyperreactivity and increased rates of arterial and venous thrombosis. SARS-CoV-2 mutations have resulted in several variants with differences in transmissibility, infectivity, and patient outcomes. This study investigates the effects of the ancestral strain of SARS-CoV-2 (WA1) and two variants of concern, Delta and Omicron, on the human megakaryocyte (MK) phenotype and transcriptome. Human CD34+-derived MKs were incubated with WA1, Delta or Omicron SARS-CoV-2 variants for 24 hours. MK activation markers were measured under resting and thrombin-stimulated conditions. RNA-seq and cytokine release in response to the viruses were assessed. Plasma cytokines were measured in hospitalized COVID-19 patients. Treatment of MKs with WA1, Delta or Omicron variants of SARS-CoV-2 resulted in similar increases in classical activation markers. However, SARS-CoV-2 variants mediated distinct transcriptomic changes. Across variants, 60 genes overlapped, including CXCL8. Consistent with transcriptomic changes, SARS-CoV-2-incubated MKs secreted significantly elevated levels of IL-8. Among hospitalized COVID-19 patients, plasma IL-8 levels were highest in COVID-19 patients who subsequently experienced thrombotic events or died. In conclusion, WA1, Delta, and Omicron similarly induce classical MK activation responses while mediating distinct transcriptomic changes. Increased IL-8 levels may serve as a biomarker to inform platelet hyperreactivity and thrombotic events associated with COVID-19.

SARS-CoV-2 infection is associated with platelet hyperreactivity and increased rates of arterial and venous thrombosis. SARS-CoV-2 mutations have resulted in several variants with differences in transmissibility, infectivity, and patient outcomes. However, the specific transcriptomic and functional changes in megakaryocytes and platelets in response to infection by different SARS-CoV-2 variants remain largely unexplored.

This study investigates how different SARS-CoV-2 variants affect the function and transcriptome of platelet precursors – megakaryocytes. Exposure of megakaryocytes to various SARS-CoV-2 variants resulted in similar activation but distinct transcriptomic changes. SARS-CoV-2 increased IL-8 levels in megakaryocytes, and elevated IL-8 levels were also observed in plasma from COVID-19 patients. Notably, plasma IL-8 levels were highest in COVID-19 patients who subsequently experienced a thrombotic event or died.

Elevated IL-8 levels in MKs, independent of SARS-CoV-2 variant type, and in the plasma of COVID-19 patients suggest that IL-8 may serve as a biomarker for platelet hyperreactivity and thrombotic events associated with COVID-19.