AUTHOR=Dunai Cordelia , Hetherington Claire , Boardman Sarah A. , Clark Jordan J. , Sharma Parul , Subramaniam Krishanthi , Tharmaratnam Kukatharmini , Needham Edward J. , Williams Robyn , Huang Yun , Wood Greta K. , Collie Ceryce , Fower Andrew , Fox Hannah , Ellul Mark A. , Held Marie , Egbe Franklyn N. , Griffiths Michael , Solomon Tom , Breen Gerome , Kipar Anja , Cavanagh Jonathan , Irani Sarosh R. , Vincent Angela , Stewart James P. , Taams Leonie S. , Menon David K. , Michael Benedict D. TITLE=Pulmonary SARS-CoV-2 infection leads to para-infectious immune activation in the brain JOURNAL=Frontiers in Immunology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1440324 DOI=10.3389/fimmu.2024.1440324 ISSN=1664-3224 ABSTRACT=

Neurological complications, including encephalopathy and stroke, occur in a significant proportion of COVID-19 cases but viral protein is seldom detected in the brain parenchyma. To model this situation, we developed a novel low-inoculum K18-hACE2 mouse model of SARS-CoV-2 infection during which active viral replication was consistently seen in mouse lungs but not in the brain. We found that several mediators previously associated with encephalopathy in clinical samples were upregulated in the lung, including CCL2, and IL-6. In addition, several inflammatory mediations, including CCL4, IFNγ, IL-17A, were upregulated in the brain, associated with microglial reactivity. Parallel in vitro experiments demonstrated that the filtered supernatant from SARS-CoV-2 virion exposed brain endothelial cells induced activation of uninfected microglia. This model successfully recreates SARS-CoV-2 virus-associated para-infectious brain inflammation which can be used to study the pathophysiology of the neurological complications and the identification of potential immune targets for treatment.