TY - JOUR
T1 - Dysregulation of the leukocyte signaling landscape during acute COVID-19
AU - Turnbull, Isaiah R.
AU - Fuchs, Anja
AU - Remy, Kenneth E.
AU - Kelly, Michael P.
AU - Frazier, Elfaridah P.
AU - Ghosh, Sarbani
AU - Chang, Shin Wen
AU - Mazer, Monty B.
AU - Hess, Annie
AU - Leonard, Jennifer M.
AU - Hoofnagle, Mark H.
AU - Colonna, Marco
AU - Hotchkiss, Richard S.
N1 - Publisher Copyright:
Copyright: © 2022 Turnbull et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128306061&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0264979
DO - 10.1371/journal.pone.0264979
M3 - Article
C2 - 35421120
AN - SCOPUS:85128306061
SN - 1932-6203
VL - 17
JO - PloS one
JF - PloS one
IS - 4 April
M1 - e0264979
ER -