Megakaryocytes are a Novel SARS-CoV-2 Infection Target and Risk Factor for Mortality and Multi-Organ Failure

Discovery of a biomarker for patients at high risk of progression to severe Coronavirus Disease 2019 (COVID-19) is critical for clinical management, particularly in areas of the world where widespread vaccine distribution and herd immunity have yet to be achieved. Herein, we characterize peripheral blood from 218 COVID-19 patients with flow cytometry and provide evidence that megakaryocytes are a target for infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We demonstrate a positive correlation between infected megakaryocytes expressing the protein calprotectin (also called S100A8/A9), a known marker of COVID-19 severity. Additionally, we show that infected, calprotectin expressing megakaryocytes are correlated with COVID-19 severity and are a prognostic indicator of 30-day clinical outcomes including respiratory failure, thrombotic events, acute kidney injury (AKI), ICU admission, and mechanical ventilation. These findings represent a novel SARS-CoV-2 infection target with significant clinical implications as a biomarker for clinical outcomes associated with severe COVID-19.

Plasma microbiome in COVID-19 subjects: an indicator of gut barrier defects and dysbiosis

The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) symptoms. We asked whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n=30) and healthy control (n=16) were collected during hospitalization. Plasma microbiome was analyzed using 16S rRNA sequencing, metatranscriptomic analysis, and gut permeability markers including FABP-2, PGN and LPS in both patient cohorts. Almost 65% (9 out 14) COVID-19 patients showed abnormal presence of gut microbes in their bloodstream. Plasma samples contained predominately Proteobacteria, Firmicutes, and Actinobacteria. The abundance of gram-negative bacteria (Acinetobacter, Nitrospirillum, Cupriavidus, Pseudomonas, Aquabacterium, Burkholderia, Caballeronia, Parabhurkholderia, Bravibacterium, and Sphingomonas) was higher than the gram-positive bacteria (Staphylococcus and Lactobacillus) in COVID-19 subjects. The levels of plasma gut permeability markers FABP2 (1282{+/-}199.6 vs 838.1{+/-}91.33; p=0.0757), PGN (34.64{+/-}3.178 vs 17.53{+/-}2.12; p<0.0001), and LPS (405.5{+/-}48.37 vs 249.6{+/-}17.06; p=0.0049) were higher in COVID-19 patients compared to healthy subjects. These findings support that the intestine may represent a source for bacteremia and may contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.