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 4

Corticosteroid treatment is associated with reductions in T cell and myeloid cell chemokine expression predominantly in monocyte-derived alveolar macrophages.

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Corticosteroid treatment is associated with reductions in T cell and mye...
(A) Box plots of cytokine expression for all BAL fluid and plasma cytokines exhibiting significantly altered expression (q < 0.05, Mann-Whitney) following corticosteroid treatment. Lightly shaded boxes represent cytokine expression values prior to corticosteroid treatment, and darkly shaded boxes represent expression values after corticosteroid treatment. (B) Paired comparisons of cytokine expression in BAL and plasma for all paired samples (paired Mann-Whitney). (C) Deconvolution of “bulk” cytokine expression in BAL fluid by scRNA-Seq of cells isolated from BAL fluid. Mean cytokine gene expression for each cell type detected in scRNA-Seq data (33) (black points) is overlaid on bulk cytokine expression by multiplexed cytokine array (filled bars) to identify cell type contributors to cytokine expression. MoAM, monocyte-derived alveolar macrophage; TRAM, tissue-resident alveolar macrophage; Treg, CD4+ regulatory T cell; iNKT, invariant natural killer T cell.