Circulating SARS-CoV-2⁺ megakaryocytes are associated with severe viral infection in COVID-19

Journal Article · 08 August 2023 · Blood Advances

DOI: https://doi.org/10.1182/bloodadvances.2022009022 · OSTI ID:2471614

Fortmann, Seth D. ^[1]; Patton, Michael J.  ^[1]; Frey, Blake F.  ^[1]; Tipper, Jennifer L. ^[1]; Reddy, Sivani B.  ^[1]; Vieira, Cristiano P. ^[1]; Hanumanthu, Vidya Sagar ^[1]; Sterrett, Sarah ^[1]; Floyd, Jason L.  ^[1]; Prasad, Ram  ^[1]; Zucker, Jeremy D.  ^[2]; Crouse, Andrew B.  ^[1]; Huls, Forest ^[1]; Chkheidze, Rati  ^[1]; Li, Peng  ^[1]; Erdmann, Nathaniel B. ^[1]; Harrod, Kevin S.  ^[1]; Gaggar, Amit ^[1]; Goepfert, Paul A. ^[1]; Grant, Maria B.  ^[1] ; Might, Matthew  ^[1]

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1. University of Alabama at Birmingham, AL (United States)
2. Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation frequencies with clinical outcomes. Using peripheral blood, we show that megakaryocytes are increased in the systemic circulation in COVID-19, and we identify and validate S100A8/A9 as a defining marker of megakaryocyte dysfunction. We further reveal a subpopulation of S100A8/A9⁺ megakaryocytes that contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein and RNA. Using flow cytometry of peripheral blood and in vitro studies on SARS-CoV-2–infected primary human megakaryocytes, we demonstrate that megakaryocytes can transfer viral antigens to emerging platelets. Mechanistically, we show that SARS-CoV-2–containing megakaryocytes are nuclear factor κB (NF-κB)-activated, via p65 and p52; express the NF-κB–mediated cytokines interleukin-6 (IL-6) and IL-1β; and display high surface expression of Toll-like receptor 2 (TLR2) and TLR4, canonical drivers of NF-κB. In a cohort of 218 inpatients with COVID-19, we correlate frequencies of megakaryocyte subpopulations with clinical outcomes and show that SARS-CoV-2–containing megakaryocytes are a strong risk factor for mortality and multiorgan injury, including respiratory failure, mechanical ventilation, acute kidney injury, thrombotic events, and intensive care unit admission. Furthermore, we show that SARS-CoV-2⁺ megakaryocytes are present in lung and brain autopsy tissues from deceased donors who had COVID-19. To our knowledge, this study offers the first evidence implicating SARS-CoV-2⁺ peripheral megakaryocytes in severe disease and suggests that circulating megakaryocytes warrant investigation in inflammatory disorders beyond COVID-19.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
• Sponsoring Organization: National Institutes of Health (NIH); USDOE
• Grant/Contract Number: AC05-76RL01830
• OSTI ID: 2471614
• Report Number(s): PNNL-SA--162329
• Journal Information: Blood Advances, Journal Name: Blood Advances Journal Issue: 15 Vol. 7; ISSN 2473-9529
• Publisher: American Society of HematologyCopyright Statement
• Country of Publication: United States
• Language: English