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. 2021 Mar 18:8:600881.
doi: 10.3389/fmolb.2021.600881. eCollection 2021.

Circulating Nucleosomes as Potential Markers to Monitor COVID-19 Disease Progression

Etienne Cavalier  1 , Julien Guiot  2 , Katharina Lechner  3   4 , Alexander Dutsch  3   4 , Mark Eccleston  5 , Marielle Herzog  5 , Thomas Bygott  5 , Adrian Schomburg  6   7   8 , Theresa Kelly  9 , Stefan Holdenrieder  10
Affiliations

Circulating Nucleosomes as Potential Markers to Monitor COVID-19 Disease Progression

Etienne Cavalier et al. Front Mol Biosci. .

Abstract

The severity of coronavirus disease 2019 (COVID-19) varies significantly with cases spanning from asymptomatic to lethal with a subset of individuals developing Severe Acute Respiratory Syndrome (SARS) and death from respiratory failure. To determine whether global nucleosome and citrullinated nucleosome levels were elevated in COVID-19 patients, we tested two independent cohorts of COVID-19 positive patients with quantitative nucleosome immunoassays and found that nucleosomes were highly elevated in plasma of COVID-19 patients with a severe course of the disease relative to healthy controls and that both histone 3.1 variant and citrullinated nucleosomes increase with disease severity. Elevated citrullination of circulating nucleosomes is indicative of neutrophil extracellular trap formation, neutrophil activation and NETosis in severely affected individuals. Importantly, using hospital setting (outpatient, inpatient or ICU) as a proxy for disease severity, nucleosome levels increased with disease severity and may serve as a guiding biomarker for treatment. Owing to the limited availability of mechanical ventilators and extracorporal membrane oxygenation (ECMO) equipment, there is an urgent need for effective tools to rapidly assess disease severity and guide treatment selection. Based on our studies of two independent cohorts of COVID-19 patients from Belgium and Germany, we suggest further investigation of circulating nucleosomes and citrullination as biomarkers for clinical triage, treatment allocation and clinical drug discovery.

Keywords: biomarkers; COVID-19; NETosis; SARS nucleosomes; citrullination; liquid biopsy; neutrophil extracellular traps.

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Conflict of interest statement

Volition Companies are commercial developers of Nu.Q™ assays. AS and SH are SAB member and paid consultant to Belgian Volition. ME is a paid consultant to, shareholder in, and an inventor on issued and pending patents assigned to Belgian Volition. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Detection of circulating nucleosomes associated with H3.1 or H3R8Cit in plasma of COVID-19 patients. Plasma from COVID-19 patients (n = 35), Non-COVID-19 patients (n = 10) and controls collected before the COVID -19 outbreak (n = 50) were assayed with Nu. Q H3.1 (A) or Nu.Q H3R8Cit (B). COVID-19 patients were compared with Non-COVID-19 patients or control patients and Non-COVID-19 patients with controls by a Wilcoxon-Mann-Whitney test; ****p-value <0.001; *p-value <0.05, ns = no significant difference.
FIGURE 2
FIGURE 2
Circulating H3.1 Nucleosomes and H3R8 Citrullinated nucleosomes in plasma of COVID-19 and Non-COVID-19 patients admitted to ICU, Normal Ward or Outpatients/ER. Plasma concentrations of H3.1 Nucleosomes (A) and H3R8 Citrullinated nucleosomes (B) from 38 Non-COVID and 14 COVID-19 patients. H3.1 Nucleosomes (C) and H3R8 Citrullinated nucleosomes (D) levels from Non-COVID-19 and COVID-19 patient compared within each hospital setting (Outpatient/emergency room (ER), Regular Ward and Intensive Care Unit (ICU). Plasma from COVID-19 patients admitted to Intensive Care Unit (ICU) (n = 6); Regular ward (n = 3) or Outpatient/ER (n = 5) were assayed with H3.1 Nucleosome levels (E) and H3R8 Citrullinated nucleosomes (F). Patients groups were compared by a Wilcoxon-Mann-Whitney test, *p-value <0.05, ns = no significant difference.
FIGURE 3
FIGURE 3
IL-6 and CRP levels in COVID-19 patients admitted to ICU, Normal Ward or Outpatient/ER. Plasma from COVID-19 patients admitted to Intensive Care Unit (ICU) (n = 6); Regular ward (n = 3) or Outpatient/emergency room (ER) (n = 5) were assayed with IL-6 (A) and CRP (B). Patients groups were compared by a Wilcoxon-Mann-Whitney test, * p-value <0.05, ***p-value <0.01, ns = no significant difference.
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