Neurological complications and infection mechanism of SARS-COV-2

Abstract

Currently, SARS-CoV-2 has caused a global pandemic and threatened many lives. Although SARS-CoV-2 mainly causes respiratory diseases, growing data indicate that SARS-CoV-2 can also invade the central nervous system (CNS) and peripheral nervous system (PNS) causing multiple neurological diseases, such as encephalitis, encephalopathy, Guillain-Barré syndrome, meningitis, and skeletal muscular symptoms. Despite the increasing incidences of clinical neurological complications of SARS-CoV-2, the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established. In this review, we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence. Finally, we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion. These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.

Fig. 1

SARS-CoV-2-associated neurological symptoms. A variety of neurological manifestations are present in COVID-19 patients, such as encephalitis, encephalopathy, ageusia, anosmia, Miller Fisher syndrome, and Guillain-Barré syndrome

Fig. 2

SARS-CoV-2 may invade the brain through the olfactory nerve. SARS-CoV-2 infects the olfactory epithelium via the ACE2 receptor. The olfactory epithelium surrounds horizontal basal cells with ACE2 receptor. Human horizontal basal cells express ACE2, suggesting they can be infected by SARS-CoV-2. Horizontal basal cells can further mature into olfactory neurons. We propose that infected horizontal basal cells can mature into SARS-CoV-2-infected olfactory neurons. These infected olfactory neurons share a synaptic connection with neurons in the olfactory bulb (OB). This may allow for viral spread from the periphery into the CNS. The OB has many connections throughout the brain. This allows for rapid viral transit to many areas of the brain

Fig. 3

SARS-CoV-2 possibly directly infects vascular endothelial cells via the ACE2 or NRP1 receptors. Viral particles in the bloodstream can reach the brain through the blood–brain barrier (BBB) by infecting and replicating inside brain microvascular endothelial cells. Infection of neurons by SARS-CoV-2 and the increased BBB permeability could be responsible for severe neurological symptoms in COVID-19

Fig. 4

SARS-CoV-2 infection can cause excessive peripheral immune responses to result in BBB dysfunction. a The cytokine storms with remarkable BBB permeability effects may allow the virus or infected immune cells reach the brain. b Possible CNS pathological mechanisms caused by the severe peripheral hyperinflammation associated with COVID-19. The infected immune cells invade in brain and release cytokines to activate glial cells to release pro-inflammatory cytokines and VEGF which could cause severe neurological symptoms in COVID-19