Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19
Rogan A. Grant, Taylor A. Poor, Lango Sichizya, Estefani Diaz, Joseph I. Bailey, Sahil Soni, Karolina J. Senkow, Xóchitl G. Pérez-Leonor, Hiam Abdala-Valencia, Ziyan Lu, Helen K. Donnelly, Lacy M. Simons, Egon A. Ozer, Robert M. Tighe, Jon W. Lomasney, Richard G. Wunderink, Benjamin D. Singer, Alexander V. Misharin, G.R. Scott Budinger, for The Northwestern University Successful Clinical Response In Pneumonia Therapy (NU SCRIPT) Investigators
Rogan A. Grant, Taylor A. Poor, Lango Sichizya, Estefani Diaz, Joseph I. Bailey, Sahil Soni, Karolina J. Senkow, Xóchitl G. Pérez-Leonor, Hiam Abdala-Valencia, Ziyan Lu, Helen K. Donnelly, Lacy M. Simons, Egon A. Ozer, Robert M. Tighe, Jon W. Lomasney, Richard G. Wunderink, Benjamin D. Singer, Alexander V. Misharin, G.R. Scott Budinger, for The Northwestern University Successful Clinical Response In Pneumonia Therapy (NU SCRIPT) Investigators
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Clinical Research and Public Health COVID-19 Immunology

Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19

Abstract

BACKGROUND Survivors of pneumonia, including SARS-CoV-2 pneumonia, are at increased risk for cognitive dysfunction and dementia. In rodent models, cognitive dysfunction following pneumonia has been linked to the systemic release of lung-derived pro-inflammatory cytokines. Microglia are poised to respond to inflammatory signals from the circulation, and their dysfunction has been linked to cognitive impairment in murine models of dementia and in humans.METHODS We measured levels of 55 cytokines and chemokines in bronchoalveolar lavage fluid and plasma from 341 patients with respiratory failure and 13 healthy controls, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. We used flow cytometry to sort neuroimmune cells from postmortem brain tissue from 5 patients who died from COVID-19 and 3 patients who died from other causes for single-cell RNA-sequencing.RESULTS Microglia from patients with COVID-19 exhibited a transcriptomic signature suggestive of their activation by circulating pro-inflammatory cytokines. Peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, but cumulative cytokine exposure was higher in patients with COVID-19. Treatment with corticosteroids reduced expression of COVID-19–specific cytokines.CONCLUSION Prolonged lung inflammation results in sustained elevations in circulating cytokines in patients with SARS-CoV-2 pneumonia compared with those with pneumonia secondary to other pathogens. Microglia from patients with COVID-19 exhibit transcriptional responses to inflammatory cytokines. These findings support data from rodent models causally linking systemic inflammation with cognitive dysfunction in pneumonia and support further investigation into the role of microglia in pneumonia-related cognitive dysfunction.FUNDING SCRIPT U19AI135964, UL1TR001422, P01AG049665, P01HL154998, R01HL149883, R01LM013337, R01HL153122, R01HL147290, R01HL147575, R01HL158139, R01ES034350, R01ES027574, I01CX001777, U01TR003528, R21AG075423, T32AG020506, F31AG071225, T32HL076139.

Authors

Rogan A. Grant, Taylor A. Poor, Lango Sichizya, Estefani Diaz, Joseph I. Bailey, Sahil Soni, Karolina J. Senkow, Xóchitl G. Pérez-Leonor, Hiam Abdala-Valencia, Ziyan Lu, Helen K. Donnelly, Lacy M. Simons, Egon A. Ozer, Robert M. Tighe, Jon W. Lomasney, Richard G. Wunderink, Benjamin D. Singer, Alexander V. Misharin, G.R. Scott Budinger, for The Northwestern University Successful Clinical Response In Pneumonia Therapy (NU SCRIPT) Investigators

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Figure 3

Cumulative but not peak exposure to pro-inflammatory cytokines is higher in patients with severe SARS-CoV-2 pneumonia compared with patients with severe pneumonia secondary to other pathogens.

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Cumulative but not peak exposure to pro-inflammatory cytokines is higher...
(A) Hierarchical clustering of cumulative exposure to 44 BAL cytokines showing significant variability by diagnosis (q < 0.05, Kruskal-Wallis) from 327 patients estimated by geometric integration of the levels of 479 BAL samples collected throughout the duration of mechanical ventilation. LTAC, long-term acute care. (B) Hierarchical clustering of cumulative exposure to 51 plasma cytokines showing significant variability by diagnosis (q < 0.05, Kruskal-Wallis) from 258 patients estimated by geometric integration of the levels of 396 plasma samples collected throughout the duration of mechanical ventilation. (C) Cumulative expression of selected pro-inflammatory cytokines in BAL fluid from A. (D) Cumulative expression of selected pro-inflammatory cytokines in plasma from B. (E) Schematic for calculation of cumulative exposure for each cytokine assayed for each patient throughout the course of mechanical ventilation by geometric integration. BAL samples from 3 patients and plasma samples from 2 patients receiving long-term mechanical ventilation were excluded from these analyses.