COVID, complement, and the brain

Abstract

The brains of COVID-19 patients are affected by the SARS-CoV-2 virus, and these effects may contribute to several COVID-19 sequelae, including cognitive dysfunction (termed "long COVID" by some researchers). Recent advances concerning the role of neuroinflammation and the consequences for brain function are reviewed in this manuscript. Studies have shown that respiratory SARS-CoV-2 infection in mice and humans is associated with selective microglial reactivity in the white matter, persistently impaired hippocampal neurogenesis, a decrease in the number of oligodendrocytes, and myelin loss. Brain MRI studies have revealed a greater reduction in grey matter thickness in the orbitofrontal cortex and parahippocampal gyrus, associated with a greater reduction in global brain size, in those with SARS-CoV-2 and a greater cognitive decline. COVID-19 can directly infect endothelial cells of the brain, potentially promoting clot formation and stroke; complement C3 seems to play a major role in this process. As compared to controls, the brain tissue of patients who died from COVID-19 have shown a significant increase in the extravasation of fibrinogen, indicating leakage in the blood-brain barrier; furthermore, recent studies have documented the presence of IgG, IgM, C1q, C4d, and C5b-9 deposits in the brain tissue of COVID-19 patients. These data suggest an activation of the classical complement pathway and an immune-mediated injury to the endothelial cells. These findings implicate both the classical and alternative complement pathways, and they indicate that C3b and the C5b-9 terminal complement complex (membrane attack complex, MAC) are acting in concert with neuroinflammatory and immune factors to contribute to the neurological sequelae seen in patients with COVID.

Keywords: C5b-9; COVID; brain; cognitive dysfunction; complement system; endothelial cells.

Figure 1

SARS-CoV-2 and complement activation effect on brain endothelial cells. Immunoglobulins raised after SARS-CoV-2 infection can have direct effects on cells, but also indirect effects as shown by the activation of the complement system. All three activation pathways (classical, alternative and lectin) can be activated by the virus and lead to the formation of C3 convertase and C5 convertase. The formation of the terminal complement complex C5b-9 leads to the EC lysis or activation. Insertion of sublytic C5b-9 on EC lead to the activation of cell signaling pathways important in cell proliferation (ERK1 and PI3K pathway), the release of growth factors (PDGF, bFGF, PIGF) and cytokines (IL-1, IL-6, IL-8, MCP1). Subsequent to EC activation and lysis the infiltration of macrophages and T cells occurs, followed by activation of astrocytes and microglia and leakage of plasma proteins as a consequence of BBB changes and subsequent neuronal dysfunction. All these changes lead to brain dysfunction seen in long COVID syndrome (Created with BioRender.com).