Enterovirus infection and its relationship with neurodegenerative diseases

Neurodegenerative diseases (NDs) are increasingly common, especially in populations with higher life expectancies. They are associated mainly with protein metabolism and structure changes, leading to neuronal cell death. Viral infections affect these cellular processes and may be involved in the etiology of several neurological illnesses, particularly NDs. Enteroviruses (EVs) frequently infect the central nervous system (CNS), causing neurological disease. Inflammation, disruption of the host autophagy machinery, and deregulation and accumulation/misfolding of proteins are the main alterations observed after infection by an EV. In this perspective, we discuss the most recent findings on the subject, examining the possible role of EVs in the development of NDs, and shedding light on the putative role played by these viruses in developing NDs.

Key words:
enterovirus; neurodegenerative diseases; amyotrophic lateral sclerosis; Alzheimer’s disease; Parkinson’s disease

Authorship

Ivanildo Pedro Sousa Junior⁺+ Corresponding author: ivanildo.sousa@ioc.fiocruz.br

All authors participated in the writing, editing, and content management of this manuscript and declare no conflicts of interest

Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Virologia Molecular, Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz-FiocruzBrazilRio de Janeiro, RJ, BrazilFundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Virologia Molecular, Rio de Janeiro, RJ, Brasil

https://orcid.org/0000-0003-1840-3302

Tuane Cristine Ramos Gonçalves Vieira

All authors participated in the writing, editing, and content management of this manuscript and declare no conflicts of interest

Universidade Federal do Rio de Janeiro, Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Estrutural, Rio de Janeiro, RJ, BrasilUniversidade Federal do Rio de JaneiroBrazilRio de Janeiro, RJ, BrazilUniversidade Federal do Rio de Janeiro, Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Estrutural, Rio de Janeiro, RJ, Brasil

+ Corresponding author: ivanildo.sousa@ioc.fiocruz.br

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Figures | Tables

Figures (2)
Tables (1)

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Fig. 1:
mechanisms leading to neurodegenerative diseases after virus infection. Virus infection can collectively trigger different alterations in cell processes through three main mechanisms: 1. It alters protein metabolism, perturbing protein synthesis and degradation (protein ubiquitination, degradation at the proteasome, and autophagy/aggrephagy). It also affects chaperon prevention/correction of protein misfolding. 2. Viruses can directly interact with proteins, leading to structural conversion, starting aggregation, and forming small toxic aggregates and amyloid fibrils. These fibrils can seed monomer aggregation, representing a self-replicating process. Different virus molecules, such as proteins, lipids, and nucleic acids, are supposed to show this property. 3. Viruses perturb post-translational protein modifications, modulating protein function and oligomerisation. For example, Tau hyperphosphorylation, associated with Alzheimer’s disease, can be triggered by a virus infection, leading to the formation of neurofibrillary tangles and cell dysfunction. This figure was designed at Biorender.com.

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Fig. 2:
the potential effect of enterovirus (EV) infections in neural cells and its impact on developing neurodegenerative diseases (NDs). (A) After gaining access to the central nervous system (CNS), EV infects neural cells, leading to different alterations in cell processes and decreasing the number of neurons. (B) EV infection could stimulate neural cells to produce amyloid proteins as defense mechanisms, wrapping and neutralising the virus. These amyloid proteins constitute the amyloid plaques, which activate microglia releasing pro-inflammatory cytokines. (C) The blood-brain barrier (BBB) can be disturbed from outside the brain via peripheral inflammatory mediators and dysbiosis, as well as from within the brain by the mediators generated by neural cells that have been stimulated by EV infections.

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TABLE
Overview of some neurodegenerative conditions

Fig. 1: mechanisms leading to neurodegenerative diseases after virus infection. Virus infection can collectively trigger different alterations in cell processes through three main mechanisms: 1. It alters protein metabolism, perturbing protein synthesis and degradation (protein ubiquitination, degradation at the proteasome, and autophagy/aggrephagy). It also affects chaperon prevention/correction of protein misfolding. 2. Viruses can directly interact with proteins, leading to structural conversion, starting aggregation, and forming small toxic aggregates and amyloid fibrils. These fibrils can seed monomer aggregation, representing a self-replicating process. Different virus molecules, such as proteins, lipids, and nucleic acids, are supposed to show this property. 3. Viruses perturb post-translational protein modifications, modulating protein function and oligomerisation. For example, Tau hyperphosphorylation, associated with Alzheimer’s disease, can be triggered by a virus infection, leading to the formation of neurofibrillary tangles and cell dysfunction. This figure was designed at Biorender.com.

Fig. 2: the potential effect of enterovirus (EV) infections in neural cells and its impact on developing neurodegenerative diseases (NDs). (A) After gaining access to the central nervous system (CNS), EV infects neural cells, leading to different alterations in cell processes and decreasing the number of neurons. (B) EV infection could stimulate neural cells to produce amyloid proteins as defense mechanisms, wrapping and neutralising the virus. These amyloid proteins constitute the amyloid plaques, which activate microglia releasing pro-inflammatory cytokines. (C) The blood-brain barrier (BBB) can be disturbed from outside the brain via peripheral inflammatory mediators and dysbiosis, as well as from within the brain by the mediators generated by neural cells that have been stimulated by EV infections.

TABLE Overview of some neurodegenerative conditions

NDs-types	Main associated disease	Neuropathologies	Protein aggregates
Prion diseases	Creutzfeldt-Jakob disease	Spongiform changes	PrP
Tauopathies	Alzheimer’s disease	Neuritic plaques neurofibrillary tangles	Tau and Aβ
Tauopathies	Pick’s disease	Pick body	Tau
Synucleinopathies	Lewy body disorders	Lewy bodies	α-Synuclein
Synucleinopathies	Parkinson’s disease	Lewy neurites	α-Synuclein
Transactive response DNA-binding protein 43 (TDP-43) proteinopathies	Amyotrophic lateral sclerosis	Motor neuron loss	TDP-43
Inclusion			TDP-43

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[1] + Corresponding author: ivanildo.sousa@ioc.fiocruz.br