Neurotropic virus infection and neurodegenerative diseases: Potential roles of autophagy pathway

Abstract

Neurodegenerative diseases (NDs) constitute a group of disorders characterized by the progressive deterioration of nervous system functionality. Currently, the precise etiological factors responsible for NDs remain incompletely elucidated, although it is probable that a combination of aging, genetic predisposition, and environmental stressors participate in this process. Accumulating evidence indicates that viral infections, especially neurotropic viruses, can contribute to the onset and progression of NDs. In this review, emerging evidence supporting the association between viral infection and NDs is summarized, and how the autophagy pathway mediated by viral infection can cause pathological aggregation of cellular proteins associated with various NDs is discussed. Furthermore, autophagy-related genes (ARGs) involved in Herpes simplex virus (HSV-1) infection and NDs are analyzed, and whether these genes could link HSV-1 infection to NDs is discussed. Elucidating the mechanisms underlying NDs is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of NDs.

Keywords: Alzheimer's disease; Parkinson's disease; autophagy; neurodegenerative diseases; neurotropic virus.

FIGURE 1

Potential mechanisms of viral infections in ND pathogenesis. Neurotropic viruses can enter the CNS via a “Trojan horse” mechanism or altered vascular permeability. Once in the CNS, virus infection enhances the expression of proteins associated with NDs, which can reduce the nucleation barrier for protein aggregation. HSV‐1 infection activates GSK3β, PKA, and PKR. Among them, GSK3β and PKA are responsible for Tau phosphorylation, while PKR catalyzes eIF2α phosphorylation, leading to BACE1 translation and Aβ accumulation. Viral surfaces or specific viral proteins and antibodies can interact with proteins associated with NDs, ultimately leading to their deposition. BACE1, β‐site amyloid precursor protein cleaving enzyme 1; CNS, central nervous system; eIF2α, elongation initiation factor 2α; GSK3β, glycogen synthase kinase 3β; HSV‐1, Herpes simplex virus type 1; NDs, neurodegenerative diseases; PKA, protein kinase A; PKR, RNA‐activated protein kinase.

FIGURE 2

Virus infection mediates the autophagy process. Viral infection inhibits autophagy initiation by activation of the type I PI3K‐AKT–mTOR pathway or the interaction of viral proteins, ICP34.5, Bcl‐2, TRS1, and IRS1, with Beclin 1; HSV‐1 Us3 targets Ulk1 also to hinder autophagy initiation by the class III PI3K‐VPS34‐Beclin 1 pathway; HSV‐1 hinders autophagy by targeting PKR or TRIM23‐TBK1 complex; CVB3, EBV, and KSHV exploit autophagosomes for viral replication; CVB3 proteinase 3C targets host proteins, SNAP29, PLEKHM1, STX17, and TFEB, to inhibit autophagy; IAV M2 impedes autophagosome‐lysosome fusion. CVB3, Coxsackievirus B3; EBV, Epstein‐Barr virus; HSV‐1, Herpes simplex virus type 1; IAV, Influenza A virus; KSHV, Kaposi's sarcoma‐associated herpesvirus; PLEKHM1, pleckstrin homology domain containing protein family member 1; SNAP29, synaptosome associated protein 29; STX17, syntaxin 17; TFEB, transcription factor EB.

FIGURE 3

Potential mechanisms of autophagy pathway mediated by virus infection in NDs pathogenesis. HSV‐1 ICP34.5 interacts with Beclin 1 to hinder autophagosome formation by promoting the dephosphorylation of eIF2α; IAV H1N1, CVB3, and SARS‐CoV 2 can inhibit autophagy; oxidative stress induced by HSV‐1 triggers autophagosomes accumulation, inefficient of autophagosome‐lysosome fusion, inhibition of cathepsin activity; HIV Vpr affects SNAPIN expression that is involved in lysosomal maturation; CCL3, CCL4, and CCL5 bind and activate HIV receptor CCR5, which in turn promotes mTORC1 activation by the PI3K‐AKT‐TSC2 pathway and inhibits autophagy; autophagy dysfunction prevents the degradation of α‐syn, Aβ, tau, and HTT, ultimately contributing to NDs pathology. Autophagy dysfunction activates ER stress and triggers the UPR that can activate GSK‐3β to phosphorylate tau protein; PERK inhibitor GSK2606414 reduce tau phosphorylation following HHV‐6A infection. Autophagy reduction and UPR activation caused by HHV‐6A infection is related to the activation of pro‐inflammatory pathways, including the STAT3, NF‐kB and mTOR pathways, leading to the release of inflammatory cytokines such as IL‐6, IL‐1β, and CXCL13, further promoting neuroinflammation; HSV‐2 infection reduces the C9ORF72 level that is responsible for triggering TBK1 phosphorylation and aggregation to induce TDP‐43 aggregation. C9ORF72, chromosome 9 open reading frame 72; CVB3, Coxsackievirus B3; ER, endoplasmic reticulum; GSK3β, glycogen synthase kinase 3β; HHV‐6A, Human herpesvirus 6 A; HIV, Human immunodeficiency virus; HSV‐1, Herpes simplex virus type 1; IAV, Influenza A virus; NDs, neurodegenerative diseases; PERK, protein kinase R‐like endoplasmic reticulum kinase; SARS‐CoV‐2, Severe acute respiratory syndrome coronavirus 2; TDP‐43, TAR DNA‐binding protein 43; UPR, unfolded protein response.

FIGURE 4

Differentially expressed genes (DEGs) in the HSV‐1‐infected cells from the SGE124118 dataset. (A, B) The numbers of up‐regulated and down‐regulated DEGs in the HSV‐1‐infected cells. (C) Intersection of DEGs and autophagy‐related genes upon HSV‐1 infection. (D) Bubble map of the top 20 most enriched signaling pathways.

FIGURE 5

Autophagy‐related genes in NDs. Gene interaction network of autophagy‐related genes and host genes associated with NDs from MalaCards DB. The network was built using Cytoscape v.3.8.0.