SpringerLink
Log in

The Analysis of Herpes Simplex Virus Type 1 (HSV-1)-Encoded MicroRNAs Targets: A Likely Relationship of Alzheimer's Disease and HSV-1 Infection

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alzheimer's disease (AD), the most frequently diagnosed dementia, is a senile neurodegenerative disorder characterized by amnesia and cognitive dysfunction. Unfortunately, there are still no successful strategies to prevent AD progression. Thus, the vast majority of research focuses on recognizing risk factors for develo** and progressing this disease. Human spirochetes, fungi, Borrelia burgdorferi, Chlamydophila pneumoniae, Helicobacter pylori, and human herpes simplex virus type 1 (HSV-1) have all been implicated in the development and progression of AD. Identifying microRNAs (miRs) encoded by DNA viruses has indicated that viruses can be evolved to exploit RNA silencing to regulate host and viral genes. Similar to host miR, v-miR can interact with the 3′ untranslated region (UTR) of the target mRNA to regulate gene expression. Although HSV-1 can also encode various miRs, their significance in the development and progression of AD is still unclear. In the present study, utilizing the bioinformatics approach (R software and related packages), we analyzed the differentially expressed genes (DEGs) in AD samples (grey matter) of GSE37263 dataset obtained from the NCBI Gene Expression Omnibus (GEO). Then, the sequences of HSV-1-encoded-miRs were retrieved from miRbase, and their targets were predicted by miRDB. Afterward, the common genes between downregulated DEGs in AD and targets of HSV-1-encoded miRs were identified to shed new light on the relationship between HSV-1 infection and AD development. Our results have indicated that HSV-1-encoded-miRs can target the downregulated DEGs in AD, and these aberrant interactions can offer valuable diagnostic/prognostic biomarkers for affected patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Consent for Publication and Data Availability

All the authors accept the publication of this manuscript. The data is completely available from Nima Hemmat and Haniyeh Asadzadeh, as the first authors, as well as Dr. Behzad Baradaran, as the corresponding author.

References

  • Agostini S, Mancuso R, Baglio F, Clerici M (2017) A protective role for herpes simplex virus type-1-specific humoral immunity in Alzheimer’s disease. Expert Rev Anti-Infect Ther 15:89–91

    Article  CAS  PubMed  Google Scholar 

  • Apostolova LG (2016) Alzheimer disease. Continuum (Minneap Minn) 22:419–434. https://doi.org/10.1212/CON.0000000000000307

    Article  Google Scholar 

  • Arias B et al (2014) DISC1-TSNAX and DAOA genes in major depression and citalopram efficacy. J Affect Disord 168:91–97. https://doi.org/10.1016/j.jad.2014.06.048

    Article  CAS  PubMed  Google Scholar 

  • Ball MJ (1982) Limbic predilection in Alzheimer dementia: is reactivated herpes virus involved? Can J Neurol Sci 9:303–306

    Article  CAS  PubMed  Google Scholar 

  • Barbu MG et al (2020) MicroRNA involvement in signaling pathways during viral infection. Front Cell Dev Biol 8:143. https://doi.org/10.3389/fcell.2020.00143

    Article  PubMed  PubMed Central  Google Scholar 

  • Bello-Morales R, Andreu S, Lopez-Guerrero JA (2020) The role of herpes simplex virus type 1 infection in demyelination of the central nervous system. Int J Mol Sci 21:5026. https://doi.org/10.3390/ijms21145026

    Article  CAS  PubMed Central  Google Scholar 

  • Bradshaw MJ, Venkatesan A (2016) Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics 13:493–508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruscella P, Bottini S, Baudesson C, Pawlotsky J-M, Feray C, Trabucchi M (2017) Viruses and miRNAs: more friends than foes. Front Microbiol 8:824

    Article  PubMed  PubMed Central  Google Scholar 

  • Bylund J, Zhang C, Harder DR (2002) Identification of a novel cytochrome P450, CYP4X1, with unique localization specific to the brain. Biochem Biophys Res Commun 296:677–684

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Wang X (2020) miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res 48:D127–D131. https://doi.org/10.1093/nar/gkz757

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Zheng J, Li X, Zhu L, Shao Z, Yan X, Zhu X (2020) Wdr47 controls neuronal polarization through the Camsap family microtubule minus-end-binding proteins. Cell Rep 31:107526

    Article  CAS  PubMed  Google Scholar 

  • Cui C et al (2006) Prediction and identification of herpes simplex virus 1-encoded microRNAs. J Virol 80:5499–5508. https://doi.org/10.1128/JVI.00200-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cullen BR (2011) Viruses and microRNAs: RISCy interactions with serious consequences. Genes Dev 25:1881–1894. https://doi.org/10.1101/gad.17352611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis S, Meltzer PS (2007) GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics 23:1846–1847

    Article  PubMed  Google Scholar 

  • De Chiara G et al (2019) Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLoS Pathog 15:e1007617

    Article  PubMed  PubMed Central  Google Scholar 

  • Dehhaghi M, Kazemi Shariat Panahi H, Guillemin GJ (2018) Microorganisms’ footprint in neurodegenerative diseases. Front Cell Neurosci 12:466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20:307–315

    Article  CAS  PubMed  Google Scholar 

  • Götz J, Bodea L-G, Goedert M (2018) Rodent models for Alzheimer disease. Nat Rev Neurosci 19:583–598

    Article  PubMed  Google Scholar 

  • Hajjari SN, Mehdizadeh M, Sadigh-Eteghad S, Shanehbandi D, Teimourian S, Baradaran B (2017) Secretases-related miRNAs in Alzheimer’s disease: new approach for biomarker discovery. Neurol Sci 38:1921–1926

    Article  PubMed  Google Scholar 

  • Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658

    Article  CAS  PubMed  Google Scholar 

  • Harris SA, Harris EA (2018) Molecular mechanisms for herpes simplex virus type 1 pathogenesis in Alzheimer’s disease. Front Aging Neurosci 10:48

    Article  PubMed  PubMed Central  Google Scholar 

  • Hennah W et al (2009) DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry 14:865–873. https://doi.org/10.1038/mp.2008.22

    Article  CAS  PubMed  Google Scholar 

  • Hsu M-H, Savas Ü, Griffin KJ, Johnson EF (2007) Human cytochrome p450 family 4 enzymes: function, genetic variation and regulation. Drug Metab Rev 39:515–538

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148:1204–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huber W et al (2015) Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods 12:115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itzhaki RF (2018) Corroboration of a major role for herpes simplex virus type 1 in Alzheimer’s disease. Front Aging Neurosci 10:324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kannan M et al (2017) WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy. Proc Natl Acad Sci USA 114:E9308–E9317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karim S et al (2014) The role of viruses in neurodegenerative and neurobehavioral diseases. CNS Neurol Disord Drug Targets Former Curr Drug Targets CNS Neurol Disord 13:1213–1223

    CAS  Google Scholar 

  • Katic J, Loers G, Tosic J, Schachner M, Kleene R (2017) The cell adhesion molecule CHL1 interacts with patched-1 to regulate apoptosis during postnatal cerebellar development. J Cell Sci 130:2606–2619

    CAS  PubMed  Google Scholar 

  • Kearns CA, Ravanelli AM, Cooper K, Appel B (2015) Fbxw7 limits myelination by inhibiting mTOR signaling. J Neurosci 35:14861–14871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khalilzadeh B, Rashidi M, Soleimanian A, Tajalli H, Kanberoglu GS, Baradaran B, Rashidi M-R (2019) Development of a reliable microRNA based electrochemical genosensor for monitoring of miR-146a, as key regulatory agent of neurodegenerative disease. Int J Biol Macromol 134:695–703

    Article  CAS  PubMed  Google Scholar 

  • Köroğlu Ç, Baysal L, Cetinkaya M, Karasoy H, Tolun A (2013) DNAJC6 is responsible for juvenile Parkinsonism with phenotypic variability. Parkinsonism Relat Disord 19:320–324

    Article  PubMed  Google Scholar 

  • La Rosa F et al (2019) Herpes simplex virus-1 (HSV-1) infection induces a potent but ineffective IFN-λ production in immune cells of AD and PD patients. J Transl Med 17:1–10

    Google Scholar 

  • Li J et al (2017) Molecular dissection of neuroligin 2 and Slitrk3 reveals an essential framework for GABAergic synapse development. Neuron 96:808-826.e808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • López-Romero P (2011) Pre-processing and differential expression analysis of Agilent microRNA arrays using the AgiMicroRna Bioconductor library. BMC Genomics 12:1–8

    Article  Google Scholar 

  • Mancuso R, Sicurella M, Agostini S, Marconi P, Clerici M (2019) Herpes simplex virus type 1 and Alzheimer’s disease: link and potential impact on treatment. Expert Rev Anti-Infect Ther 17:715–731

    Article  CAS  PubMed  Google Scholar 

  • Martin C, Solís L, Concha MI, Otth C (2011) Herpes simplex virus type 1 as risk factor associated to Alzheimer disease. Rev Med Chile 139:779–786

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP (2004) Infectious agents and age-related neurodegenerative disorders. Ageing Res Rev 3:105–120

    Article  PubMed  Google Scholar 

  • Mishra R, Kumar A, Ingle H, Kumar H (2020) The interplay between viral-derived miRNAs and host immunity during infection. Front Immunol 10:3079

    Article  PubMed  PubMed Central  Google Scholar 

  • Montojo J et al (2010) GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop. Bioinformatics 26:2927–2928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naqvi AR, Shango J, Seal A, Shukla D, Nares S (2018) Herpesviruses and MicroRNAs: new pathogenesis factors in oral infection and disease? Front Immunol 9:2099

    Article  PubMed  PubMed Central  Google Scholar 

  • Palo OM et al (2007) Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments. Hum Mol Genet 16:2517–2528

    Article  CAS  PubMed  Google Scholar 

  • Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47–e47

    Article  PubMed  PubMed Central  Google Scholar 

  • Shannon P et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharifi F, Fakhrzadeh H, Varmaghani M, Arzaghi SM, Khoei MA, Farzadfar F, Tanjani PT (2016) Prevalence of dementia and associated factors among older adults in Iran: National Elderly Health Survey (NEHS). Arch Iran Med 19(12):838–844

    PubMed  Google Scholar 

  • Smith TF (2008) Diversity of WD-repeat proteins. In: The coronin family of proteins. Springer, Berlin, pp 20–30

  • Snyder JL, Kearns CA, Appel B (2012) Fbxw7 regulates Notch to control specification of neural precursors for oligodendrocyte fate. Neural Dev 7:1–12

    Article  Google Scholar 

  • Takahashi H et al (2012) Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction. Nat Neurosci 15:389–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan MG, Chua WT, Esiri MM, Smith AD, Vinters HV, Lai MK (2010) Genome wide profiling of altered gene expression in the neocortex of Alzheimer’s disease. J Neurosci Res 88:1157–1169

    CAS  PubMed  Google Scholar 

  • Uchoa MF, Moser VA, Pike CJ (2016) Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors. Front Neuroendocrinol 43:60–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Umbach JL, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cullen BR (2008) MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature 454:780–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang F, **ang H, Fischer G, Liu Z, Dupont MJ, Hogan QH, Yu H (2016) HMG-CoA synthase isoenzymes 1 and 2 localize to satellite glial cells in dorsal root ganglia and are differentially regulated by peripheral nerve injury. Brain Res 1652:62–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB (2007) Herpes simplex virus infection causes cellular β-amyloid accumulation and secretase upregulation. Neurosci Lett 429:95–100

    Article  CAS  PubMed  Google Scholar 

  • Wulansari N et al (2021) Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson’s disease-linked DNAJC6 mutations. Sci Adv 7:eabb1540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng K, Liu Q, Wang S, Ren Z, Kitazato K, Yang D, Wang Y (2018) HSV-1-encoded microRNA miR-H1 targets Ubr1 to promote accumulation of neurodegeneration-associated protein. Virus Genes 54:343–350

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Miranda-Saksena M, Saksena NK (2013) Viruses and neurodegeneration. Virol J 10:1–17

    Article  Google Scholar 

Download references

Acknowledgements

All the authors would like to thank the Neurosciences Research Center of Tabriz University of Medical Sciences for their kind supports during this study.

Funding

This study was supported by the Immunology Research Center, Tabriz University of Medical Sciences.

Author information

Author notes

  1. Nima Hemmat and Haniyeh Asadzadeh have contributed equally to this study.

Authors and Affiliations

  1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Nima Hemmat, Zahra Asadzadeh, Mahdi Abdoli Shadbad & Behzad Baradaran

  2. Department of Psychology, Ardabil Branch of Islamic Azad University, Ardabil, Iran

    Haniyeh Asadzadeh

  3. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Mahdi Abdoli Shadbad

  4. Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Behzad Baradaran

Authors
  1. Nima Hemmat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haniyeh Asadzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zahra Asadzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahdi Abdoli Shadbad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Behzad Baradaran
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NH and HA: first authors of the manuscript, analyzing raw microarray data with R software and other bioinformatics analysis, writing the draft. ZA and MAS: Structural and grammatical editing of the manuscript, figures arrangement, and statistical analysis. BB: the corresponding author of the manuscript, creating the primary concept of the manuscript, final editing.

Corresponding author

Correspondence to Behzad Baradaran.

Ethics declarations

Conflict of interest

All the authors also declared that no personal or financial relationship with other people or organizations exists in this study.

Ethical Approval

In the current study, the data of the GSE37263 dataset, which has ethical approval, was analyzed.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hemmat, N., Asadzadeh, H., Asadzadeh, Z. et al. The Analysis of Herpes Simplex Virus Type 1 (HSV-1)-Encoded MicroRNAs Targets: A Likely Relationship of Alzheimer's Disease and HSV-1 Infection. Cell Mol Neurobiol 42, 2849–2861 (2022). https://doi.org/10.1007/s10571-021-01154-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-021-01154-8

Keywords

Search

Navigation