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Infection-induced vascular inflammation in COVID-19 links focal microglial dysfunction with neuropathologies through IL-1/IL-6-related systemic inflammatory states

ABSTRACT: COVID-19 is associated with diverse neurological- and inflammatory states that predict poor acute- and long-term outcomes in patients. However, the mechanisms whereby infection-induced inflammation could affect complex neuropathologies through microglia, the main immune cells of the brain, is unclear. We developed a unique autopsy platform allowing the integration of molecular anatomy-, protein- and mRNA data sets in post-mortem mirror blocks of brain and peripheral organ samples from COVID-19 cases. Nanoscale microscopy, single-cell RNAseq and analysis of inflammatory and metabolic signatures revealed that focal loss of microglial P2Y12R occurs at sites of virus-associated vascular inflammation together with dysregulated microglia-vascular-astrocyte interactions, Cx3Cr1-fractalkine axis deficits and mitochondrial failure in severely affected medullary autonomic nuclei, and other brain areas. Microglial dysfunction occurs at sites of excessive synapse- and myelin phagocytosis and loss of glutamatergic terminals. These changes strongly correlate with the development of a generalized, but regionally heterogenous proinflammatory response across the brain related to interleukin-1 (IL-1), IL-6, and multiorgan virus load-related systemic inflammation via virus-sensing pattern recognition receptors (PRRs) and inflammasomes. Thus, SARS-CoV-2-induced central and systemic inflammation might lead to a primarily glio-vascular failure in the brain, promoting diverse neuropathologies through different, parallel mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234720 | GEO | 2024/11/18

REPOSITORIES: GEO

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Infection-induced vascular inflammation in COVID-19 links focal microglial dysfunction with neuropathologies through IL-1/IL-6-related systemic inflammatory states

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