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

Grant, R. A.; Poor, T. A.; Sichizya, L.; Diaz, E.; Bailey, J. I.; Soni, S.; Senkow, K. J.; Perez-Leonor, X. G.; Abdala-Valencia, H.; Lu, Z.; Donnelly, H. K.; Tighe, R. M.; Lomasney, J. W.; Wunderink, R. G.; Singer, B. D.; Misharin, A. V.; Budinger, G. R. S.; The NU SCRIPT Investigators,

doi:10.1101/2023.07.28.550765

bioRxiv · 10.1101/2023.07.28.550765

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

Grant, R. A.·Poor, T. A.·Sichizya, L.·Diaz, E.·Bailey, J. I.·Soni, S.·Senkow, K. J.·Perez-Leonor, X. G.·Abdala-Valencia, H.·Lu, Z.·Donnelly, H. K.·Tighe, R. M.·Lomasney, J. W.·Wunderink, R. G.·Singer, B. D.·Misharin, A. V.·Budinger, G. R. S.·The NU SCRIPT Investigators,

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Abstract

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia1-4. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans5. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-[a] and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-196, was associated with lower levels of CXCL10, CCL8, and CCL2--molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells7. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.

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Grant, R. A., Poor, T. A., Sichizya, L., Diaz, E., Bailey, J. I., Soni, S., Senkow, K. J., Perez-Leonor, X. G., Abdala-Valencia, H., Lu, Z., Donnelly, H. K., Tighe, R. M., Lomasney, J. W., Wunderink, R. G., Singer, B. D., Misharin, A. V., Budinger, G. R. S., The NU SCRIPT Investigators,. 2023-07-28. Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19. https://doi.org/10.1101/2023.07.28.550765

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