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.
| Original language | English (US) |
|---|---|
| Article number | e178859 |
| Journal | JCI Insight |
| Volume | 9 |
| Issue number | 8 |
| DOIs | |
| State | Published - 2024 |
Funding
SCRIPT U19AI135964, UL1TR001422, P01AG049665, P01HL154998, R01HL149883, R01LM013337, R01HL153122, R01HL147290, R01HL147575, R01HL158139, R01ES034350, R01ES027574, I01CX001777, U01TR003528, R21AG075423, T32AG020506, F31AG071225, T32HL076139. We would like to thank Constadina Arvanitis in the Northwestern University Center for Advanced Microscopy & Nikon Imaging Center for substantial help with optimization of combined RNAScope and immunofluorescence on human brain samples. The Northwestern University Flow Cytometry Core Facility, Northwestern University Metabolomics Core Facility, and Northwestern University Center for Advanced Microscopy were supported by Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We further thank Cara J. Gottardi for her insightful comments on smFISH image presentation and analysis. Finally, we thank the many human participants and their families for their invaluable contributions to this research. The Genomics Compute Cluster is part of Quest, Northwestern University's high-performance computing facility, with the purpose to advance research in genomics. ScRNA-Seq was performed with support from Simpsons Querrey Institute for Epigenetics. Cell sorting was performed on a BD FACSAria SORP cell sorter purchased through the support of NIH 1S10OD011996-01. Additional funding was provided by SQLIFTS at Northwestern University, Dixon Translational Research Grants Initiative, UL1TR001422, Chicago Biomedical Consortium, P01AG049665, P01HL154998, R01HL149883, R01LM013337, R01HL153122, R01HL147290, R01HL147575, R01HL158139, R01ES034350, R01ES027574, I01CX001777, U01TR003528, R21AG075423, T32AG020506, F31AG071225, and T32HL076139. See Supplemental Acknowledgments for details on The NU SCRIPT Investigators. We would like to thank Constadina Arvanitis in the Northwestern University Center for Advanced Microscopy & Nikon Imaging Center for substantial help with optimization of combined RNAScope and immunofluorescence on human brain samples. The Northwestern University Flow Cytometry Core Facility, Northwestern University Metabolomics Core Facility, and Northwestern University Center for Advanced Microscopy were supported by Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We further thank Cara J. Gottardi for her insightful comments on smFISH image presentation and analysis. Finally, we thank the many human participants and their families for their invaluable contributions to this research. The Genomics Compute Cluster is part of Quest, Northwestern University\u2019s high-performance computing facility, with the purpose to advance research in genomics. ScRNA-Seq was performed with support from Simpsons Querrey Institute for Epigenetics. Cell sorting was performed on a BD FACSAria SORP cell sorter purchased through the support of NIH 1S10OD011996-01. Additional funding was provided by SQLIFTS at Northwestern University, Dixon Translational Research Grants Initiative, UL1TR001422, Chicago Biomedical Consortium, P01AG049665, P01HL154998, R01HL149883, R01LM013337, R01HL153122, R01HL147290, R01HL147575, R01HL158139, R01ES034350, R01ES027574, I01CX001777, U01TR003528, R21AG075423, T32AG020506, F31AG071225, and T32HL076139. See Supplemental Acknowledgments for details on The NU SCRIPT Investigators.
ASJC Scopus subject areas
- General Medicine
