Does SARS-CoV-2 affect neurodegenerative disorders? TLR2, a potential receptor for SARS-CoV-2 in the CNS

Abstract

The coronavirus (COVID-19) pandemic, caused by severe acute respiratory system coronavirus 2 (SARS-CoV-2), has created significant challenges for scientists seeking to understand the pathogenic mechanisms of SARS-CoV-2 infection and to identify the best therapies for infected patients. Although ACE2 is a known receptor for the virus and has been shown to mediate viral entry into the lungs, accumulating reports highlight the presence of neurological symptoms resulting from infection. As ACE2 expression is low in the central nervous system (CNS), these neurological symptoms are unlikely to be caused by ACE2-virus binding. In this review, we will discuss a proposed interaction between SARS-CoV-2 and Toll-like receptor 2 (TLR2) in the CNS. TLR2 is an innate immune receptor that recognizes exogenous microbial components but has also been shown to interact with multiple viral components, including the envelope (E) protein of SARS-CoV-2. In addition, TLR2 plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Based on these observations, we hypothesize that TLR2 may play a critical role in the response to SARS-CoV-2 infiltration in the CNS, thereby resulting in the induction or acceleration of AD and PD pathologies in patients.

Fig. 1. Representative immunohistochemical analysis of innate and adaptive immune cells in the frontal cortex of control and SARS-CoV-2-infected patients.

White matter sections obtained from one control and two SARS-CoV-2-infected patients were immunostained with anti-IBA-1 and anti-TMEM119 for microglia and anti-CD3 for T cells. Scale bars represent 50 μm.

Fig. 2. Potential entry routes for SARS-CoV-2 into the central nervous system (CNS).

SARS-CoV-2 can infiltrate the CNS via the penetration of the blood-brain barrier (BBB), the blood-cerebrospinal fluid barrier in the epithelium of the choroid plexus, the corneal epithelium of the eye, the olfactory epithelium of the olfactory bulb (nasal route), and the peripheral nervous system, including the mucosal epithelium, enterocytes, and smooth muscle cells.

Fig. 3. Potential interaction mechanism of SARS-CoV-2 and TLR2 in AD and PD.

E protein of brain-infiltrated SARS-CoV-2 induces microglial TLR2, thereby increasing the susceptibility of TLR2 to α-syn and Aβ oligomers. The activation of microglial TLR2 by the E protein of SARS-CoV-2, α-syn, or Aβ increases the release of neurotoxic, proinflammatory cytokines, which may also induce vascular degeneration in the brain, thereby increasing SARS-CoV-2 infiltration into the CNS. In neurons, the E protein of SARS-CoV-2 may activate neuronal TLR2, which impairs neuronal autophagic processes, resulting in an accumulation of neurotoxic α-syn aggregates.

Fig. 4. Representative immunohistochemical analysis of phosphorylated-α-syn in the frontal cortex of control and SARS-CoV-2-infected patients.

White matter sections obtained from one control and two SARS-CoV-2-infected patients were immunostained with anti-phospho-α-syn. The arrowhead represents the LN-like accumulation of phospho-α-syn (p-S129). Scale bar represents 50 μm.