SARS-CoV-2 and Multiple Sclerosis: Potential for Disease Exacerbation

Abstract

While the respiratory tract is the primary route of entry for SARS-CoV-2, evidence shows that the virus also impacts the central nervous system. Intriguingly, case reports have documented SARS-CoV-2 patients presenting with demyelinating lesions in the brain, spinal cord, and optic nerve, suggesting possible implications in neuroimmune disorders such as multiple sclerosis (MS) and other related neuroimmune disorders. However, the cellular mechanisms underpinning these observations remain poorly defined. The goal of this paper was to review the literature to date regarding possible links between SARS-CoV-2 infection and neuroimmune demyelinating diseases such as MS and its related disorders, with the aim of positing a hypothesis for disease exacerbation. The literature suggests that SARS-CoV, SARS-CoV-2, and orthologous murine coronaviruses invade the CNS via the olfactory bulb, spreading to connected structures via retrograde transport. We hypothesize that a glial inflammatory response may contribute to damaged oligodendrocytes and blood brain barrier (BBB) breakdown, allowing a second route for CNS invasion and lymphocyte infiltration. Potential for molecular mimicry and the stimulation of autoreactive T cells against myelin is also described. It is imperative that further studies on SARS-CoV-2 neuroinvasion address the adverse effects of the virus on myelin and exacerbation of MS symptoms, as nearly 3 million people suffer from MS worldwide.

Keywords: COVID-19; SARS-CoV-2; adaptive immunity; blood-brain barrier; cytokine storm; experimental autoimmune encephalomyelitis; multiple sclerosis; neuroinflammation.

Figure 1

Neurotropism of SARS-CoV-2. Upon inhalation, SARS-CoV-2 can reach the brain parenchyma via two mechanisms. Following the olfactory route, SARS-CoV-2 infects the olfactory epithelium (1) directly under the cribiform plate (2). The virus can then traverse the cribiform plate through its foramina or via the olfactory nerves, gaining access to the olfactory bulb (3) and spreading to first and second order connections throughout the brain. Additionally, SARS-CoV-2 may be inhaled into the lungs, reach the alveoli (4) and gain access into the blood stream (5). A hematogenous route of SARS-CoV-2 neuroinvasion can then occur following breach of the BBB. Once inside the brain parenchyma, neurons and glial cells such as astrocytes have been shown to be directly infected. Oligodendrocytes and OPCs have shown similar infection with the coronavirus strain MHV.

Figure 2

SARS-CoV-2 impacts the glial landscape. Once inside the brain parenchyma, SARS-CoV-2 can alter the neural microenvironment by impacting glial cell function. Infected oligodendrocytes can result in neurodegeneration (1), leading to inaccurate remyelination by surviving oligodendrocytes (2). Inhibited OPC differentiation (3) further impairs the remyelination process, as new oligodendrocytes are not formed. While activated microglia secrete proinflammatory cytokines that are damaging to neural tissue, microglial apoptosis reduces myelin debris clearance (4), further suppressing remyelination potential. Lastly, activated astrocytes may secrete neurotoxic soluble factors (5) that can impair neuronal viability and damage axons.

Figure 3

SARS-CoV-2 Damages the Blood Brain Barrier from the “Inside-Out” as well as from the “Outside-In.” Neurotropic infection triggers the activation of glial cells and a proinflammatory response that damages the BBB from within the CNS (inside-out). This is supported by evidence of basement membrane disruption without tight junction alteration, as well as altered cerebral vasculature without direct endothelial cell infection. In contrast, evidence of disrupted or absent tight junctions, as well as upregulated ICAM and VCAM on endothelial cells suggests an outside-in mechanism that allows the diapedesis of autoreactive T cells from the blood, through the BBB, and into the brain. Contracted pericyte morphology coupled with upregulated ICAM and ACE-2 expression also suggests an outside-in mechanism.

Figure 4

Peripheral immune activation and molecular mimicry against myelin. The adaptive immune response to SARS-CoV-2 may result in the activation of CNS-autoreactive T cells as a result of molecular mimicry. Cytokine storm, observed in SARS-CoV-2 infected individuals, could then elicit the differentiation of CNS-antigen-specific Th17 cells. The upregulation of IL-6, IL-17, and TNF-α is of particular interest, as these cytokines are heavily linked to MS and other demyelinating disorders in mouse and man such as NMOSD and EAE. Further research is needed to understand the Th1 response and generation of IFN-γ in response to COVID-19, as literature suggests mixed results.