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

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.

Increased Histone-DNA Complexes and Endothelial-Dependent Thrombin Generation in Severe COVID-19

“…This is consistent with prior reports of elevated NETs in COVID-19, as evidenced by increased cell-free DNA, myeloperoxidase-DNA complexes, and citrullinated-Histone H3 [21][22][23]. Similar observations were recently made in two independent cohorts of COVID-19 positive patients with a quantitative nucleosome immunoassay that measured cell-free H3.1 nucleosomes [24]. These investigators demonstrated 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 the histone 3.1 variant and citrullinated nucleosomes increase with disease severity.…”

Patients with COVID-19: in the dark-NETs of neutrophils

“…Increased serum levels of neutrophil-derived MPO-DNA and citrullinated histone H3, both NET degradation products, closely parallel lung distress and predict COVID-19 severity [ 52 ]. Furthermore, circulating nucleosomes were identified as potential markers to monitor COVID-19 disease progression [ 119 ]. Immature and low-density neutrophils predominate in severe COVID-19 [ 15 , 16 , 120 ].…”

PAD Inhibitors as a Potential Treatment for SARS-CoV-2 Immunothrombosis

“…Some isozymes of PAD, including PADI1 and PADI6, were elevated but to a less significant degree. Inspection of nucleosomes levels in SARS-CoV-2 infected patients [ 17 ] further corresponds with the elevations observed in DVT-induced mice. Patients diagnosed with COVID-19 were observed to have elevated levels of histone variant H3.1 and H3R8 compared to controls, more prominently among patients admitted into intensive care units (ICU) compared to non-ICU patients positive for COVID-19 [ 17 ].…”

“…Inspection of nucleosomes levels in SARS-CoV-2 infected patients [ 17 ] further corresponds with the elevations observed in DVT-induced mice. Patients diagnosed with COVID-19 were observed to have elevated levels of histone variant H3.1 and H3R8 compared to controls, more prominently among patients admitted into intensive care units (ICU) compared to non-ICU patients positive for COVID-19 [ 17 ]. The increased NETs and associated turnover products described in prior studies are evidenced to assist in occlusion of vasculature, notably pulmonary vessels [ 5 ].…”