Open AccessDysregulation of the leukocyte signaling landscape during acute COVID-19
Author(s) -
Isaiah R. Turnbull,
Anja Fuchs,
Kenneth E. Remy,
Michael P. Kelly,
Elfaridah P. Frazier,
Subham Ghosh,
Soo-Eun Chang,
Monty Mazer,
Annie Hess,
Jennifer Leonard,
Mark H. Hoofnagle,
Marco Colonna,
Richard S. Hotchkiss
Publication year - 2022
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0264979
Subject(s) - immune system , immunology , biology , inflammation , immune dysregulation , myeloid , t cell , signal transduction , mass cytometry , microbiology and biotechnology , phenotype , biochemistry , gene
The global COVID-19 pandemic has claimed the lives of more than 750,000 US citizens. Dysregulation of the immune system underlies the pathogenesis of COVID-19, with inflammation mediated tissue injury to the lung in the setting of suppressed systemic immune function. To define the molecular mechanisms of immune dysfunction in COVID-19 we utilized a systems immunology approach centered on the circulating leukocyte phosphoproteome measured by mass cytometry. We find that although COVID-19 is associated with wholesale activation of a broad set of signaling pathways across myeloid and lymphoid cell populations, STAT3 phosphorylation predominated in both monocytes and T cells. STAT3 phosphorylation was tightly correlated with circulating IL-6 levels and high levels of phospho-STAT3 was associated with decreased markers of myeloid cell maturation/activation and decreased ex-vivo T cell IFN-γ production, demonstrating that during COVID-19 dysregulated cellular activation is associated with suppression of immune effector cell function. Collectively, these data reconcile the systemic inflammatory response and functional immunosuppression induced by COVID-19 and suggest STAT3 signaling may be the central pathophysiologic mechanism driving immune dysfunction in COVID-19.