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

Etienne Cavalier,Adrian Schomburg,Alexander Dutsch,Katharina Lechner,Marielle Herzog,Thomas Bygott,Julien Guiot,Mark Eccleston,Stefan Holdenrieder,Theresa Kelly

doi:10.3389/fmolb.2021.600881

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.

Highlights

The emergence and rapid progression of COVID-19 to pandemic status has placed substantial strain on international health care services
Plasma H3.1 nucleosome levels were significantly increased in hospitalized COVID-19 patients compared to hospitalized non-COVID-19 patients (Figure 1A; p < 0.05) whereas H3R8 citrullinated nucleosomes did not show any significant difference between the two groups (Figure 1B)
In samples taken within 5 days of admission, there was a trend toward higher H3.1 and H3R8Cit nucleosome levels in the 25 COVID-19 patients with more advanced disease suffering from severe acute respiratory syndrome (SARS) compared to the 10 COVID-19 patients without Severe Acute Respiratory Syndrome (SARS), but the trend was not significant (Supplementary Figure S1)

Summary

Introduction

The emergence and rapid progression of COVID-19 to pandemic status has placed substantial strain on international health care services. One characteristic of the disease is the development of lifethreatening illness and alarming level of mortality (61.5%) in a subset of COVID-19 patients developing Severe Acute Respiratory Syndrome (SARS) resulting from infection with SARS-CoV-2 (Yan et al, 2020) Effective triage of these high-risk individuals represents an urgent and, so far, Circulating Nucleosomes in COVID-19 unmet clinical need to better direct appropriate resources for their care until herd immunity is established, protecting communities from future outbreaks. Viral infection can induce NETosis - a process where nucleosomal histone proteins H3, H2A, and H4 are hypercitrullinated by the nuclear enzyme PAD4 This promotes the massive decondensation of chromatin (Danthi, 2016; Mozzini and Girelli, 2020), resulting in the release of chromatin fragments into the extracellular matrix. Nucleosome levels were toxic to monocytes and the authors concluded that this may provide a mechanism for immune suppression following NET aggregation (Tsourouktsoglou et al, 2020)

Methods

Results

Conclusion