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Advanced Neurology SARS-CoV-2 in age-associated neurodegeneration

Table 3. (Continued)
SARS‑CoV‑2 Function in SARS‑CoV‑2 replication Plausible mechanism contributing References
proteins to neurodegeneration
and CXCL9; promotes cytokine production such as IL−1α,
IL−1β, IL−6, IL−8, IL−10, TNF−α, and IFNβ; inhibits the
signaling IFN-I by blocking the phosphorylation of STAT2
Orf7b Transmembrane protein promotes apoptosis via TNFR1, Increased neuronal damage 137,139
TNF-α, and caspase 8
Orf8 Downregulates MHC-I; interacts with several ER proteins; Generating ER-stress-induced 137,139
IFN-1 response antagonism; evasion of host innate ROS production and sustained
immune response neuroinflammation
Orf9a single-stranded RNA-binding protein, which displays an May promotes viral persistence and 137,139
oligosaccharide/oligonucleotide binding fold replication in the brain
Orf9b Suppression of innate immunity by targeting MAVS Mitochondrial dysfunction 98,137,139
signalosome which may cause ROS leakage
and subsequent events leading to
neurodegeneration
Orf9c Membrane-associated protein that suppresses antiviral No prominent role; may promote 137,139
response by interference with IFN signaling and antigen low-grade inflammation in the brain
presentation
Orf10 Suppress IFN signaling, inhibits antigen processing and No prominent role; may promote 137,139
presentation, complement signaling, IL-6 signaling; low-grade inflammation in the brain
degradation of MAVS
Abbreviations: ACE2: Angiotensin-converting enzyme 2; avSG: Antiviral stress granule; ATF6: Activating transcription factor 6; ATP6AP1:
ATPase H+ transporting accessory protein 1; CCL: C-C motif chemokine ligand; CD: Cluster of differentiation; CNS: Central nervous system;
CXCL9: C-X-C motif chemokine ligand 9; EIF4E2: Eukaryotic translation initiation factor 4E family member 2; GAS: GMP-AMP synthase;
GIGYF2: GRB10 interacting GYF protein 2; HIF1α: Hypoxia-inducible factor 1-alpha; IFN: Interferons; IFNAR1: Interferon alpha receptor; IFNAR2:
Interferon beta receptor; IKKε: Inhibitor of nuclear factor κB kinase; IL-1β: Interleukin-1beta; IRF: Interferon regulatory factor; ISGF: Interferon
stimulated gene factor; ISRE: Interferon stimulated response element; JAK1: Janus kinase 1; MAVS: Mitochondrial antiviral-signaling protein;
MDA5: Melanoma differentiation-associated protein 5; MHC-I: Major Histocompatibility-1; mtROS: Mitochondrial reactive oxygen species;
N: Nucleocapsid; NF-κβ: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: Nucleotide-binding domain, leucine-rich-containing
family, pyrin domain-containing-3; NPC: Nucleopore -complex; Nsp: Non-structural protein; Nup98: Nucleoporin 98; ORF: Open reading frame;
PGAM5: Phosphoglycerate mutase 5; PI3KC3-C1: Phosphatidylinositol (PI) 3-kinase complex I; PNS: Peripheral nervous system; RAE1: Ribonucleic
acid export 1; RIG-I: Retinoic acid inducible gene I; ROS: Reactive oxygen species; SARS-CoV-2: Severe acute respiratory syndrome-coronavirus-2;
SRP: Signal recognition particle; STAT: Signal transducer and activator of transcription; TBK1: TANK binding kinase; TLR: Toll-like receptors;
TNF-α: Tumor necrosis factor alpha; TNFR1: Tumor necrosis factor receptor 1; TYK2: Tyrosine kinase 2; ZNF598: Zinc finger protein 598.

T-cell responses and accelerates the clearance of persistent signatures of aging in post-COVID brains. Transcriptomic
viruses in a lymphocytic choriomeningitis virus-infected analysis of the human frontal cortex, a region central
mouse model. These observations suggest that mild or to cognitive function, revealed downregulation of
acute SARS-CoV-2 infection alters the T-cell profile genes related to synaptic function and cognition and
and increases the number of circulating immune cells, upregulation of genes involved in the immune pathways.
potentially leading to immune cell infiltration into the brain Specifically, genes encoding S100 calcium-binding
through the BBB. Emerging evidence suggests that repeated protein A9, myosin light chain 12A, and rho-related BTB
mRNA vaccination may be linked to a proinflammatory domain-containing protein 3 were upregulated, while
response and an increase in immunoglobulin G4 (IgG4) those encoding calmodulin 3, inositol polyphosphate
levels. Rather than providing protection, this rise in IgG4 4-phosphatase type I A, glutamate ionotropic receptor
could indicate immune tolerance to the spike protein, AMPA type subunit 1, and glutamate [NMDA] receptor
potentially allowing unopposed SARS-CoV-2 infection subunit 3A were downregulated, reflecting patterns
and replication by weakening natural antiviral defences. commonly observed in the aging brain. Cumulatively, the
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In addition, elevated IgG4 synthesis from repeated available data suggest a link between neuroinflammation
vaccination with high antigen doses might contribute to induced by viral persistence and the aging process.
the development of conditions such as cerebral venous However, it remains intriguing to explore how individual
sinus thrombosis, Guillain–Barré syndrome, and stroke. viral components modulate host immune mechanisms in
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A recent study by Mavrikaki et al. revealed molecular favor of viral propagation.
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Volume 3 Issue 4 (2024) 12 doi: 10.36922/an.4267