Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 118 | 2023
Perspective

Enterovirus infection and its relationship with neurodegenerative diseases

Ivanildo Pedro Sousa Junior1,+, Tuane Cristine Ramos Gonçalves Vieira2

1Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Virologia Molecular, Rio de Janeiro, RJ, Brasil
2Universidade 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

DOI: 10.1590/0074-02760220252
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ABSTRACT

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.

REFERENCES
01. Dugger BN, Dickson DW. Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol. 2017; 9(7): a028035.
02. Guzman-Martinez L, Maccioni RB, Andrade V, Navarrete LP, Pastor MG, Ramos-Escobar N. Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol. 2019; 12(10): 1008.
03. Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases (Review). Mol Med Rep. 2016; 13(4): 3391-6.
04. Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci. 2018; 21(10): 1332-40.
05. Migliore L, Coppedè F. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res. 2009; 667(1-2): 82-97.
06. Onisiforou A, Spyrou GM. Identification of viral-mediated pathogenic mechanisms in neurodegenerative diseases using networkbased approaches. Brief Bioinform. 2021; 22(6): bbab141.
07. Abbott A. Are infections seeding some cases of Alzheimer’s disease? Nature. 2020; 587(7832): 22-5.
08. Lotz SK, Blackhurst BM, Reagin KL, Funk KE. Microbial infections are a risk factor for neurodegenerative diseases. Front Cell Neurosci. 2021; 7(15): 691136.
09. Wouk J, Rechenchoski DZ, Rodrigues BCD, Ribelato EV, Faccin- Galhardi LC. Viral infections and their relationship to neurological disorders. Arch Virol. 2021; 166(3): 733-53.
10. Leblanc P, Vorberg IM. Viruses in neurodegenerative diseases: more than just suspects in crimes. PLoS Pathog. 2022; 4; 18(8): e1010670.
11. Follmer C. Viral infection-induced gut dysbiosis, neuroinflammation, and ?-synuclein aggregation: updates and perspectives on COVID-19 and neurodegenerative disorders. ACS Chem Neurosci. 2020; 11(24): 4012-6.
12. Fang P, Kazmi SA, Jameson KG, Hsiao EY. The microbiome as a modifier of neurodegenerative disease risk. Cell Host Microbe. 2020; 28(2): 201-22.
13. Chopra G, Shabir S, Yousuf S, Kauts S, Bhat SA, Mir AH, et al. Proteinopathies: deciphering physiology and mechanisms to develop effective therapies for neurodegenerative diseases. Mol Neurobiol. 2022; 59: 7513-40.
14. Muscolino E, Luoto LM, Brune W. Viral induced protein aggregation: a mechanism of immune evasion. Int J Mol Sci. 2021; 22(17): 9624.
15. Zhang X, Yu W. Heat shock proteins and viral infection. Front Immunol. 2022; 13: 947789.
16. Valerdi KM, Hage A, van Tol S, Rajsbaum R, Giraldo MI. The role of the host ubiquitin system in promoting replication of emergent viruses. Viruses. 2021; 13(3): 369.
17. Shelkovnikova TA, An H, Skelt L, Tregoning JS, Humphreys IR, Buchman VL. Antiviral immune response as a trigger of FUS proteinopathy in amyotrophic lateral sclerosis. Cell Rep. 2019; 29(13): 4496-508e4.
18. Hategan A, Bianchet MA, Steiner J, Karnaukhova E, Masliah E, Fields A, et al. HIV Tat protein and amyloid-? peptide form multifibrillar structures that cause neurotoxicity. Nat Struct Mol Biol. 2017; 24(4): 379-86.
19. Cribbs DH, Azizeh BY, Cotman CW, LaFerla FM. Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer’s A beta peptide. Biochemistry. 2000; 39(20): 5988-94.
20. Hara H, Chida J, Uchiyama K, Pasiana AD, Takahashi E, Kido H, et al. Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells. Sci Rep. 2021; 11(1): 10109.
21. Angelli JN, Passos YM, Brito JMA, Silva JL, Cordeiro Y, Vieira TCRG. Rabbit PrP is partially resistant to in vitro aggregation induced by different biological cofactors. Front Neurosci. 2021; 15: 689315.
22. Silva JL, Cordeiro Y. The “Jekyll and Hyde” actions of nucleic acids on the prion-like aggregation of proteins. J Biol Chem. 2016; 291(30): 15482-90.
23. Tetz G, Pinho M, Pritzkow S, Mendez N, Soto C, Tetz V. Bacterial DNA promotes Tau aggregation. Sci Rep. 2020; 10(1): 2369.
24. Tetz G, Tetz V. Bacterial extracellular DNA promotes ?-amyloid aggregation. microorganisms. 2021; 9(6): 1301.
25. Riek R, Eisenberg DS. The activities of amyloids from a structural perspective. Nature. 2016; 539(7628): 227-35.
26. De-Paula VJ, Radanovic M, Diniz B, Forlenza O. Alzheimer’s disease. In: Harris J, editor. Protein aggregation and fibrillogenesis in cerebral and systemic amyloid disease. Subcellular Biochemistry. Vol 65. Dordrecht: Springer; 2012.
27. Wozniak MA, Frost AL, Itzhaki RF. Alzheimer’s disease-specific tau phosphorylation is induced by herpes simplex virus type 1. J Alzheimers Dis. 2009; 16: 341-50.
28. Zambrano A, Solis L, Salvadores N, Cortés M, Lerchundi R, Otth C. Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1. J Alzheimers Dis. 2008; 14(3): 259-69.
29. Wozniak MA, Frost AL, Preston CM, Itzhaki RF. Antivirals reduce the formation of key Alzheimer’s disease molecules in cell cultures acutely infected with herpes simplex virus type 1. PLoS One. 2011; 6(10): e25152.
30. Giunta B, Hou H, Zhu Y, Rrapo E, Tian J, Takashi M, et al. HIV-1 Tat contributes to Alzheimer’s disease-like pathology in PSAPP mice. Int J Clin Exp Pathol. 2009; 2(5): 433-43.
31. Muslin C, Mac Kain A, Bessaud M, Blondel B, Delpeyroux F. Recombination in enteroviruses, a multi-step modular evolutionary process. Viruses. 2019; 11(9): 859.
32. Sousa Jr IP, Dos Santos FB, de Paula VS, Vieira TCRG, Dias HG, Barros CA, et al. Viral and prion infections associated with central nervous system syndromes in Brazil. Viruses. 2021; 13(7): 1370.
33. Suresh S, Rawlinson WD, Andrews PI, Stelzer-Braid S. Global epidemiology of nonpolio enteroviruses causing severe neurological complications: a systematic review and meta-analysis. Rev Med Virol. 2020; 30(1): e2082.
34. Majer A, McGreevy A, Booth TF. Molecular pathogenicity of enteroviruses causing neurological disease. Front Microbiol. 2020; 11: 540.
35. Chen BS, Lee HC, Lee KM, Gong YN, Shih SR. Enterovirus and encephalitis. Front Microbiol. 2020; 11: 261.
36. Piekut T, Hur?a M, Banaszek N, Szejn P, Dorszewska J, Kozubski W, et al. Infectious agents and Alzheimer’s disease. J Integr Neurosci. 2022; 21(2): 73.
37. Luo Z, Su R, Wang W, Liang Y, Zeng X, Shereen MA, et al. EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production. PLoS Pathog. 2019; 15(11): e1008142.
38. Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. Role of microglia TLRs in neurodegeneration. Front Cell Neurosci. 2018; 12: 329.
39. García-González P, Cabral-Miranda F, Hetz C, Osorio F. Interplay between the unfolded protein response and immune function in the development of neurodegenerative diseases. Front Immunol. 2018; 9: 2541.
40. Rattanakomol P, Srimanote P, Tongtawe P, Khantisitthiporn O, Supasorn O, Thanongsaksrikul J. Host neuronal PRSS3 interacts with enterovirus A71 3A protein and its role in viral replication. Sci Rep. 2022; 12(1): 12846.
41. Mohamud Y, Luo H. The intertwined life cycles of enterovirus and autophagy. Virulence. 2019; 10(1): 470-80.
42. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013; 19(8): 983-97.
43. Wang H, Yuan M, Yang E, Chen D, Su A, Wu Z. Enterovirus 71 infection induced Aquaporin-4 depolarization by increasing matrix metalloproteinase-9 activity. Neurosci Lett. 2021; 759: 136049.
44. Tamtaji OR, Behnam M, Pourattar MA, Jafarpour H, Asemi Z. Aquaporin 4: a key player in Parkinson’s disease. J Cell Physiol. 2019; 234(12): 21471-8.
45. Fulop T, Witkowski JM, Bourgade K, Khalil A, Zerif E, Larbi A, et al. Can an infection hypothesis explain the beta amyloid hypothesis of Alzheimer’s disease? Front Aging Neurosci. 2018; 10: 224.
46. Zhong M, Wang H, Yan H, Wu S, Wang K, Yang L, et al. Effects and mechanism of A?1-42 on EV-A71 replication. Virol J. 2022; 19(1): 151.
47. Jang H, Boltz DA, Webster RG, Smeyne RJ. Viral parkinsonism. Biochim Biophys Acta. 2009; 1792(7): 714-21.
48. Nielsen NM, Rostgaard K, Hjalgrim H, Aaby P, Askgaard D. Poliomyelitis and Parkinson disease. JAMA. 2002; 287(13): 1650-1.
49. Kang JH, Lin HC. Comorbidity profile of poliomyelitis survivors in a Chinese population: a population-based study. J Neurol. 2011; 258(6): 1026-33.
50. Dourmashkin RR, McCall SA, Dourmashkin N, Hannah MJ. Virus- like particles and enterovirus antigen found in the brainstem neurons of Parkinson’s disease. F1000Res. 2018; 7: 302.
51. Park SJ, Jin U, Park SM. Interaction between coxsackievirus B3 infection and ?-synuclein in models of Parkinson’s disease. PLoS Pathog. 2021; 17(10): e1010018.
52. Xue YC, Feuer R, Cashman N, Luo H. Enteroviral infection: the forgotten link to amyotrophic lateral sclerosis? Front Mol Neurosci. 2018; 11: 63.
53. Cermelli C, Vinceti M, Beretti F, Pietrini V, Nacci G, Pietrosemoli P, et al. Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7. Eur J Epidemiol. 2003; 18(2): 123-7.
54. Berger MM, Kopp N, Vital C, Redl B, Aymard M, Lina B. Detection and cellular localization of enterovirus RNA sequences in spinal cord of patients with ALS. Neurology. 2000; 54(1): 20-5.
55. Vandenberghe N, Leveque N, Corcia P, Brunaud-Danel V, Salort- Campana E, Besson G, et al. Cerebrospinal fluid detection of enterovirus genome in ALS: a study of 242 patients and 354 controls. Amyotroph Lateral Scler. 2010; 11(3): 277-82.
56. Walker MP, Schlaberg R, Hays AP, Bowser R, Lipkin WI. Absence of echovirus sequences in brain and spinal cord of amyotrophic lateral sclerosis patients. Ann Neurol. 2001; 49(2): 249-53.
57. Nix WA, Berger MM, Oberste MS, Brooks BR, McKenna-Yasek DM, Brown Jr RH, et al. Failure to detect enterovirus in the spinal cord of ALS patients using a sensitive RT-PCR method. Neurology. 2004; 62(8): 1372-7.
58. Xue YC, Liu H, Mohamud Y, Bahreyni A, Zhang J, Cashman NR, et al. Sublethal enteroviral infection exacerbates disease progression in an ALS mouse model. J Neuroinflammation. 2022; 19(1): 16.
59. Fung G, Shi J, Deng H, Hou J, Wang C, Hong A, et al. Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis. Cell Death Differ. 2015; 22(12): 2087-97.
60. Lee EB, Lee VM, Trojanowski JQ. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci. 2011; 13(1): 38-50.
61. Zhang X, Zheng Z, Shu B, Liu X, Zhang Z, Liu Y, et al. Human astrocytic cells support persistent coxsackievirus B3 infection. J Virol. 2013; 87(22): 12407-21.
62. Feuer R, Ruller CM, An N, Tabor-Godwin JM, Rhoades RE, Maciejewski S, et al. Viral persistence and chronic immunopathology in the adult central nervous system following Coxsackievirus infection during the neonatal period. J Virol. 2009; 83(18): 9356-69.

Financial support: CAPES, FAPERJ, FIOCRUZ, CNPq.
+ Corresponding author: ivanildo.sousa@ioc.fiocruz.br
ORCID https://orcid.org/ 0000-0003-1840-3302
Received 31 October 2022
Accepted 24 January 2023

HOW TO CITE
Sousa Jr IP, Vieira TCRG. Enterovirus infection and its relationship with neurodegenerative diseases. Mem Inst Oswaldo Cruz. 2023; 118: e220252.

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