The nervous system during COVID-19: Caught in the crossfire

Abstract

SARS-CoV-2, the virus that causes coronavirus disease (COVID)-19, has become a persistent global health threat. Individuals who are symptomatic for COVID-19 frequently exhibit respiratory illness, which is often accompanied by neurological symptoms of anosmia and fatigue. Mounting clinical data also indicate that many COVID-19 patients display long-term neurological disorders postinfection such as cognitive decline, which emphasizes the need to further elucidate the effects of COVID-19 on the central nervous system. In this review article, we summarize an emerging body of literature describing the impact of SARS-CoV-2 infection on central nervous system (CNS) health and highlight important areas of future investigation.

Keywords: COVID-19; NeuroCOVID; SARS-CoV-2; anosmia; neuroimmunology; neuroinflammation; olfactory system.

FIGURE 1

The expanding species tropism of SARS‐CoV‐2. SARS‐CoV‐2 is derived from zoonotic SARS‐like sarbecoronaviruses which already have the capacity to infect hamsters and human cells. Ancestral SARS‐CoV‐2 gained the furin cleavage site while replicating in an unknown host. Ancestral SARS‐CoV‐2 could infect a variety of species and SARS‐CoV‐2 variants continue to circulate in wild deer and mink. The N501Y mutation on the spike protein expanded the tropism of SARS‐CoV‐2 to mice and rats. Subsequent spike mutations have likely expanded SARS‐CoV‐2 tropism to more species. Figure created in Biorender

FIGURE 2

The S1/S2 Site and S2’ Site on the SARS‐CoV‐2 Spike Determines the Route of Infection. (A) The SARS‐CoV‐2 spike uses furin or cathepsin B to proteolytically cleave its S1/S2 site and uses TMPRSS2 or cathepsin L to further prime the S2 subunit near the S2’ site. The SARS‐CoV spike solely relies on Cathepsin B for cleavage of its S1/S2 site and is more dependent on Cathepsin L for cleavage of its S2’ site. The SARS‐CoV‐2 Delta variant gained mutations that increased the efficiency of TMPRSS2 cleavage of the S2’ site. Omicron became more reliant on cathepsin L for priming the S2 subunit and acquired 2 mutations upstream of S1/S2 that increase the efficiency of furin cleavage. (B) Ancestral SARS‐CoV‐2 spike is usually cleaved by TMPRSS2 on the plasma membrane, which leads to ACE2‐mediated binding and fusion of the virus membrane with the cell host membrane. Instead of fusing with the membrane, Omicron relies on cathepsin L to prime its S2 subunit before ACE2‐mediated fusion with the endosomal membrane. Figure created in Biorender

FIGURE 3

SARS‐CoV‐2 infection stimulates the expression of antiviral genes, while downregulating homeostatic genes, in the olfactory neuroepithelium of rodents. As SARS‐CoV‐2 infects and replicates within ACE2‐expressing sustentacular cells, gene expression of homeostatic sustentacular cell markers decreases. In response to the growing SARS‐CoV‐2 virus burden, expression of inflammasome‐related genes, including AIM2, NLRP3, RIPK3, and ZBP1, is potentiated. As sloughing and inflammation accelerates, the expression of homeostatic olfactory receptors is suppressed. During the recovery phase, elevated levels of IFN‐γ and cytotoxic granules persist in olfactory epithelium, which could be indicative of an IFN‐γ CD8⁺ population that is also observed in the olfactory neuroepithelium of COVID‐19 patients following infection. The overexpression of CXCL10, an IFN‐γ‐inducible chemokine, supports histological evidence of a large macrophage population inundating the ethmoid turbinates. Figure created in Biorender

FIGURE 4

SARS‐CoV‐2 infection along barriers of the nervous system yields an aberrant neuroimmune response. A working model of SARS‐CoV‐2 infection along the olfactory neuroepithelium (top): As SARS‐CoV‐2 rapidly infects ACE2‐expressing sustentacular cells, macrophages phagocytose extracellular virions and debris, and neutrophils extravasate into the neuroepithelium. Cytotoxic lymphocytes also migrate to the neuroepithelium, presumably to release perforin and granzyme, and remain in the neuroepithelium for months postinfection. A working model of SARS‐CoV‐2 infection along the blood‐brain barrier (BBB) of the medulla (bottom): SARS‐CoV‐2 infects endothelial cells and triggers RIPK1‐mediated cell death, thus damaging the integrity of the BBB. Fibrinogen then supposedly leaks into the parenchyma, which could lead to perivascular macrophage and microglia activation and subsequent microglia nodule‐mediated axon damage. Microglia in nodules present unidentified antigens to infiltrating CD8⁺ T cells. Figure created in Biorender