How COVID-19 affects microvessels in the brain

Abstract

This scientific commentary refers to ‘Neurovascular injury with complement activation and inflammation in COVID-19’ by Lee et al. (https://doi.org/10.1093/brain/awac151).

Figure 1

Effects of SARS-CoV-2 on brain endothelial cells. Several direct and indirect effects of SARS-CoV-2 infection on brain endothelial cells have been described and may contribute to neurological symptoms in patients suffering from COVID-19 and its sequelae. (1) Elevated levels of cytokines [e.g. tumour necrosis factor (TNF), or interleukins like IL-6 or IL-1β] activate receptors on brain endothelial cells, leading to a pro-inflammatory phenotype. In severely ill patients, a cytokine storm—dramatically increased cytokine levels—is associated with disease burden. (2) Immunoglobulins raised after SARS-CoV-2 infection can have direct effects on cells, as described for autoantibodies acting on G protein-coupled receptors (GPCR), but also indirect effects (3) as shown for the activation of the complement system. The formation of the membrane attack complex (MAC) as the ultimate effect of the classical complement cascade results in the death of the affected cell. (4) Cell death can also be induced by direct infection of endothelial cells, leading to the expression of the main protease of SARS-CoV-2 (M^pro). Consequences of cell activation or death at the endothelium include (I) infiltration of immune cells including macrophages and T cells; (II) activation of astrocytes and microglia with the latter shown to interact directly with T cells in COVID-19 patients; (III) leakage of plasma proteins such as fibrinogen as a consequence of a disturbed blood–brain barrier; and (IV) platelet aggregation causing occlusion of microvessels in the brain. Altogether, endothelial cells act as gatekeepers for the interaction of blood components with the brain parenchyma and are central to COVID-19 disease and its post-acute sequelae. Created with BioRender.com