Can SARS-CoV-2 infect the central nervous system via the olfactory bulb or the blood-brain barrier?

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China in December 2019. On February 11, the World Health Organization (WHO) announced the name for the new illness caused by SARS-CoV-2: COVID-19. By March 11, the outbreak of COVID-19 was declared a pandemic by the WHO. This virus has extensively altered daily life for many across the globe, while claiming hundreds of thousands of lives. While fundamentally a respiratory illness, many infected individuals experience symptoms that involve the central nervous system (CNS). It is likely that many of these symptoms are the result of the virus residing outside of the CNS. However, the current evidence does indicate that the SARS-CoV-2 virus can use olfactory neurons (or other nerve tracts) to travel from the periphery into the CNS, and that the virus may also enter the brain through the blood-brain barrier (BBB). We discuss how the virus may use established infection mechanisms (ACE2, NRP1, TMPRSS2, furin and Cathepsin L), as well mechanisms still under consideration (BASIGIN) to infect and spread throughout the CNS. Confirming the impact of the virus on the CNS will be crucial in dealing with the long-term consequences of the epidemic.

Fig. 1

Proposed mechanisms for an olfactory nerve mediated infection of the CNS. SARS-CoV-2 infects the olfactory epithelium via the ACE2 receptor. The olfactory epithelium surrounds ACE2 receptor containing horizontal basal cells. Human horizontal basal cells express ACE2, while in mice they have been shown to express NRP1 (human data is unavailable), suggesting they can be infected by SARS-CoV-2. Horizontal basal cells can also mature into olfactory neurons. We propose that infected horizontal basal cells mature into SARS-CoV-2 infected olfactory neurons. These infected olfactory neurons share a synaptic connection with neurons in the olfactory bulb (OB). This allows 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 in the brain. Alternatively, the infected olfactory epithelial cells release SARS-CoV-2 at the cribriform plate. The high concentration of cells combined with localized trauma (cells damaged by infection and frequent sneezing) results in viral particles being pushed through the cribriform plate. The virus can then infect local cells (mitral cells / olfactory bulb) or migrate and cause infection elsewhere.

Fig. 2

Proposed mechanism of SARS-CoV-2 brain infection via the hematogenous route. Viral particles of SARS-CoV-2 present in the lungs can infect the lung capillaries and be translocated to the pulmonary microcirculation. Viral particles in the bloodstream can then 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 as well as an increase in BBB permeability could be responsible for severe neurological symptoms in COVID 19.