Preprint Infection-induced vascular inflammation in COVID-19 links focal microglial dysfunction with neuropathologies through (...), 2023, Fekete et al

Full title:
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 abnormalities, which predict poor outcome in patients. However, the mechanisms whereby infection-induced inflammation could affect complex neuropathologies in COVID-19 are unclear. We hypothesized that microglia, the resident immune cells of brain, are centrally involved in this process.

To study this, we developed an 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 RNA sequencing and analysis of inflammatory and metabolic signatures revealed distinct mechanisms of microglial dysfunction associated with cerebral SARS-CoV-2 infection.

We observed focal loss of microglial P2Y12R 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.

While central and systemic viral load is strongly linked in individual patients, the regionally heterogenous microglial reactivity in the brain correlated with the extent of central and systemic inflammation related to IL-1 / IL-6 via virus-sensing pattern recognition receptors (PRRs) and inflammasome activation pathways. Thus, SARS-CoV-2-induced central and systemic inflammation might lead to a primarily glio-vascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

Open access: https://www.biorxiv.org/content/10.1101/2023.06.23.546214v1.full

 

Earlier this year I posted an interview with the principal investigator, Ádám Dénes in the Visegrád regional thread, you can find it here. He is one of the researchers who got funding from the Hungarian Academy of Sciences for post-covid research.