Dysregulation of the leukocyte signaling landscape during acute COVID-19.

Abstract

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.

• Authors: Isaiah R Turnbull, Anja Fuchs, Kenneth E Remy, Michael P Kelly, Elfaridah P Frazier, Sarbani Ghosh, Shin-Wen Chang, Monty B Mazer, Annie Hess, Jennifer M Leonard, Mark H Hoofnagle, Marco Colonna, Richard S Hotchkiss
• Journal: PloS one (PLoS One) Vol. 17 Issue 4 Pg. e0264979 ( 2022) ISSN: 1932-6203 [Electronic] United States
• PMID: 35421120 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• STAT3 Transcription Factor

Topics

• COVID-19
• Humans
• Monocytes (metabolism)
• Pandemics
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• T-Lymphocytes