Fig. 2

The neurovascular unit in health and coronavirus infection. a Under normal conditions the brain’s microvasculature (i.e. the blood–brain barrier, BBB) restricts the entry of most macromolecules and neurotoxins in the bloodstream from entering the brain. This protection of the neuronal tissue is achieved by the components of the neurovascular unit: endothelial cells (tightly connected by tight junction proteins), pericytes (wrapped around the endothelium), astrocytes (whose end-feet cover most of the surface area of the vasculature), and the nearby microglial cells. b Accumulating evidence suggests that coronaviruses are able to invade the brain. Here we depict two potential routs of invasion across the BBB. Coronaviruses may enter the bloodstream from the airway, and directly infect the endothelial cell of the BBB or infect monocytes that later migrate across the BBB (through ICAM-1 facilitated transcellular transport). The presence of the virus in the brain tissue will trigger an inflammatory cascade, that involves astrocyte and microglia activation, and secretion of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokines (MPC-1, MIP-1-α). At a later stage TNF-α may upregulate the release of MMPs—enzymes that degrade the tight junction proteins and allow further paracellular leakage across the BBB. Astrocytes may also undergo a transformation to express less glutamate and potassium receptors, leading to reduced glutamate and potassium clearance, and subsequent hyper-excitability and seizures