Potential Mechanisms for SARS-CoV-2 Invasion of the Central Nervous System

Discussion of proposed mechanisms of entry into the CNS by neuroinvasive pathogens can help clinicians better understand COVID-19 related illnesses.

More research is needed to investigate the structural components of the central nervous system (CNS) for viral blockade to better understand which pathways viruses, like SARS-CoV-2, exploit, according to a review of the literature published in the Journal of Neuro-Ophthalmology.

Researchers at Massachusetts General Hospital searched publication databases for studies of neurological manifestations and proposed mechanisms of COVID-19 CNS invasion.

According to the literature, up to 85% of patients with COVID-19 experience neurological complications, with a large fraction of these patients experiencing lingering symptoms beyond 90 days. These complications are highly heterogenous, including acute encephalopathy, anosmia, ageusia, headache, fatigue, memory impairment, seizure, and acute cerebrovascular disease.

The specific mechanism of these complications remains speculative. One hypothesis is viral entry of SARS-CoV-2 directly into the CNS. To do this, the virus must make it past the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Both these structures have intricate defensive architectures comprising multiple endothelial layers and proteins.

Continued research dedicated to delineating mechanisms of pathogen entry into the CNS in this era of emerging neuroinfectious diseases is needed . . .

One potential avenue for BBB or BCSFB invasion is through cellular trafficking. Infected leukocytes have the potential to facilitate CNS infection using a ‘”Trojan horse” manner of infection, as is the strategy used by HIV. Antecedent coronaviruses have the capability to infect monocytes which may interact with specific macrophage and dendritic cell subpopulations. Despite some evidence of potential, there has not been robust data to support this type of CNS invasion and most autopsy-based series have not found overwhelming support for inflammatory infiltration.

There is also the possibility for passive diffusion through intracellular spaces. This mechanism would require BBB disruption or circumvention of anatomy. This type of invasion is used by the West Nile virus (WNV) which enhances BBB permeability. In COVID-19, patients with cytokine storm have been found to have elevated albumin in cerebrospinal fluid (CSF), suggesting potential BBB disruption. However, there has been little evidence of viral RNA in CSF.

The WNV also can infiltrate the brain via the olfactory bulb. Previous coronaviruses have demonstrated CNS entry capability in this manner, particularly in animal model studies. Given the high prevalence of patients presenting with anosmia, transolfactory spread could be a viable mechanism of entry, however, robust evidence to support this hypothesis are not available. Most published autopsy data show normal appearing olfactory bulbs.

The researchers concluded, “The neuroinvasive potential of SARS-CoV-2 has been a major topic of discussion since the start of the pandemic; at this time, most evidence suggests that direct viral entry into the CNS is a rare phenomenon in humans and would not explain the neurological symptoms experienced by millions of people with COVID-19. […] Continued research dedicated to delineating mechanisms of pathogen entry into the CNS in this era of emerging neuroinfectious diseases is needed, and persistent surveillance of viral genetic material in neuroanatomical spaces via deep sequencing is essential while we remain in this current pandemic, and for rapid detection of future outbreaks.”


Valizadeh N, Rudmann EA, Solomon IH, Mukerji SS. Mechanisms of Entry Into the Central Nervous System by Neuroinvasive Pathogens. J Neuroophthalmol. 2022;42(2):163-172. doi:10.1097/WNO.0000000000001455