Identification of viral-mediated pathogenic mechanisms in neurodegenerative diseases using network-based approaches
Open accessPublished version of a preprint
Abstract
During the course of a viral infection, virus–host protein–protein interactions (PPIs) play a critical role in allowing viruses to replicate and survive within the host. These interspecies molecular interactions can lead to viral-mediated perturbations of the human interactome causing the generation of various complex diseases. Evidences suggest that viral-mediated perturbations are a possible pathogenic etiology in several neurodegenerative diseases (NDs). These diseases are characterized by chronic progressive degeneration of neurons, and current therapeutic approaches provide only mild symptomatic relief; therefore, there is unmet need for the discovery of novel therapeutic interventions. In this paper, we initially review databases and tools that can be utilized to investigate viral-mediated perturbations in complex NDs using network-based analysis by examining the interaction between the ND-related PPI disease networks and the virus–host PPI network. Afterwards, we present our theoretical-driven integrative network-based bioinformatics approach that accounts for pathogen–genes–disease-related PPIs with the aim to identify viral-mediated pathogenic mechanisms focusing in multiple sclerosis (MS) disease. We identified seven high centrality nodes that can act as disease communicator nodes and exert systemic effects in the MS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways network. In addition, we identified 12 KEGG pathways, 5 Reactome pathways and 52 Gene Ontology Immune System Processes by which 80 viral proteins from eight viral species might exert viral-mediated pathogenic mechanisms in MS. Finally, our analysis highlighted the Th17 differentiation pathway, a disease communicator node and part of the 12 underlined KEGG pathways, as a key viral-mediated pathogenic mechanism and a possible therapeutic target for MS disease.
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Infections with neurotropic pathogens, including alphaviruses, contribute to the development of neurodegenerative diseases.
“Evidence suggests infections with neurotropic pathogens, including alphaviruses, contribute to the development of neurodegenerative diseases (Onisiforou and Spyrou, 2021).”
From Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model (2024) · cites this paper as Onisiforou and Spyrou, 2021
The Introduction says viral infections are possible risk factors for several neurodegenerative diseases and that certain neurotropic viruses may be involved in their development. But the paper does not identify alphaviruses as an example: its Table 4 lists them in connection with rheumatoid arthritis, not a neurodegenerative disease. (LLM, conf=0.88)
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BackgroundThe Infectious Etiology of Alzheimer’s Disease
Sochocka, M., Zwolińska, K., & Leszek, J. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170313122937 · Cited by 399 · see citing works
Epstein–Barr virus and virus human protein interaction maps
Calderwood, M. A., Venkatesan, K., Xing, L., Chase, M. R., Vazquez, A., Holthaus, A. M., Ewence, A. E., Li, N., Hirozane-Kishikawa, T., Hill, D. E., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702332104 · Cited by 388 · cited 1× · see citing works
“The most common properties used for the investigation of virus-host interactions are: node degree, degree centrality, betweenness centrality, shortest path and modularity score [62, 63, 67, 90, 91].”
BackgroundTh17 Cell, the New Player of Neuroinflammatory Process in Multiple Sclerosis
Jadidi‐Niaragh, F., & Mirshafiey, A. (2011) · Scandinavian Journal of Immunology · doi:10.1111/j.1365-3083.2011.02536.x · Cited by 388 · cited 1× · see citing works
“The relapsing-remitting MS phase of MS involves the infiltration of CD4+ T cells with Th1 and Th17 proinflammatory phenotype [103,104], thus highlighting the role of the Th17 cell differentiation pathway in the immunopathogenesis of MS.”
BackgroundVitamin D and Multiple Sclerosis: A Comprehensive Review
Sintzel, M., Rametta, M., & Reder, A. (2017) · Neurological Therapeutics · doi:10.1007/s40120-017-0086-4 · Cited by 385 · see citing works
Hepatitis C virus infection protein network
de Chassey, B., Navratil, V, Tafforeau, L., Hiet, M. S., Aublin‐Gex, A., Agaugué, S., Meiffren, G., Pradezynski, F., Faria, B. F., Chantier, T., et al. (2008) · Molecular Systems Biology · doi:10.1038/msb.2008.66 · Cited by 384 · cited 2× · see citing works
“The most common properties used for the investigation of virus-host interactions are: node degree, degree centrality, betweenness centrality, shortest path and modularity score [62, 63, 67, 90, 91].”
BackgroundT‐helper 17 cells expand in multiple sclerosis and are inhibited by interferon‐β
Durelli, L., Conti, L., Clerico, M., Boselli, D., Contessa, G., Ripellino, P., Ferrero, B., Eid, P., & Novelli, F. (2009) · Annals of Neurology · doi:10.1002/ana.21652 · Cited by 374 · see citing works
Lai, W. (2007) · Canadian Medical Association Journal · doi:10.1503/cmaj.071316 · Cited by 362
The Landscape of Human Proteins Interacting with Viruses and Other Pathogens
Dyer, M. D., Murali, T. M., & Sobral, B. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.0040032 · Cited by 326 · cited 1× · see citing works
“The most common properties used for the investigation of virus-host interactions are: node degree, degree centrality, betweenness centrality, shortest path and modularity score [62, 63, 67, 90, 91].”
BackgroundGenetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases
Migliore, L., & Coppedè, F. (2008) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2008.10.011 · Cited by 319 · see citing works
Alstead, S. (2020) · Encyclopedia of Personality and Individual Differences · doi:10.1016/s0001-2092(08)70357-0 · Cited by 319
Gut microbiota in neurodegenerative disorders
Sarkar, S. R., & Banerjee, S. (2019) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2019.01.004 · Cited by 319 · see citing works
Viral Trigger for Type 1 Diabetes
Filippi, C. M., & von Herrath, M. (2008) · Diabetes · doi:10.2337/db07-1023 · Cited by 312 · see citing works
Neurotropic virus infections as the cause of immediate and delayed neuropathology
Ludlow, M., Kortekaas, J., Herden, C., Hoffmann, B., Tappe, D., Trebst, C., Griffin, D., Brindle, H. E., Solomon, T., Brown, A. S., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1511-3 · Cited by 297 · cited 1× · see citing works
“Infection by certain neurotropic viruses can also lead to the formation of neuropathological and/or immunopathological lesions with the pattern of the resulting lesions having similar distribution as that of the common NDs [48, 49].”
BackgroundJang, H., Boltz, D. A., Webster, R. G., & Smeyne, R. J. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.08.001 · Cited by 289 · cited 2× · see citing works
“Similar to WNV, parkinsonian-like symptoms can also be caused by other viruses of the Flaviviridae family [21, 32], including Japanese encephalitis virus [33] and Saint Louis encephalitis virus [34].”
BackgroundEpstein-Barr virus in autoimmune diseases.
Toussirot, E., & Roudier, J. (2008) · Baillière's Best Practice & Research : Clinical Rheumatology · doi:10.1016/j.berh.2008.09.007 · Cited by 285 · see citing works
The Commensal Microbiota and Viral Infection: A Comprehensive Review
Li, N., Ma, W., Pang, M., Fan, Q., & Hua, J.-L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01551 · Cited by 282 · see citing works
Clinical Manifestations and Outcomes of West Nile Virus Infection
Sejvar, J. (2014) · Viruses · doi:10.3390/v6020606 · Cited by 279 · cited 1× · see citing works
“In addition, infection with West Nile virus (WNV), a neurotropic virus of the Flaviviridae family that causes meningoencephalitis, can also result in the development of Parkinson-like symptoms that usually resolve over time [29, 30]; however, in some cases, the symptoms can persist, resulting in chronic PD [31].”
BackgroundViral immune evasion: a masterpiece of evolution
Vossen, M. T., Westerhout, E. M., Söderberg-Nauclér, C., & Wiertz, E. (2002) · Immunogenetics · doi:10.1007/s00251-002-0493-1 · Cited by 279 · cited 2× · see citing works
“In addition, through the evolutionary process, viruses have developed an array of adaptive immune evasion strategies including interfering with antigen presentation and mimicking immune processes [43].”
BackgroundGLay: community structure analysis of biological networks
Su, G., Kuchinsky, A., Morris, J., States, D., & Meng, F. (2010) · Bioinform. · doi:10.1093/bioinformatics/btq596 · Cited by 273 · see citing works
HPIDB 2.0: a curated database for host–pathogen interactions
Ammari, M., Gresham, C. R., McCarthy, F., & Nanduri, B. (2016) · Database J. Biol. Databases Curation · doi:10.1093/database/baw103 · Cited by 270 · see citing works
TissueEnrich: Tissue-specific gene enrichment analysis
Jain, A., & Tuteja, G. (2018) · Bioinform. · doi:10.1093/bioinformatics/bty890 · Cited by 268 · cited 1× · see citing works
“e du/) [156] to perform tissue-specific gene enrichment analysis to identify possible tissues where the virus–disease interaction could manifest leading to the dysregulation of the identified pathways.”
BackgroundHuman Endogenous Retroviruses in Neurological Diseases
Küry, P., Nath, A., Créange, A., Dolei, A., Marche, P., Gold, J., Giovannoni, G., Hartung, H., & Perron, H. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.02.007 · Cited by 267 · cited 1× · see citing works
“Moreover, analysis of blood and brain samples of patients with ALS indicated increased expression of HERV-K, and experimental evidence revealed that infection of neurons with HERV-K can result in motor dysfunction in transgenic mice [37, 38].”
BackgroundViral immune modulators perturb the human molecular network by common and unique strategies
Pichlmair, A., Kandasamy, K., Alvisi, G., Mulhern, O., Sacco, R., Habjan, M., Binder, M., Stefanovic, A., Eberle, C.-A., Goncalves, A., et al. (2012) · Nature · doi:10.1038/nature11289 · Cited by 262 · see citing works
Weiner, H. L. (2008) · Journal of Neurology · doi:10.1007/s00415-008-1002-8 · Cited by 256 · cited 1× · see citing works
“The relapsing-remitting MS phase of MS involves the infiltration of CD4+ T cells with Th1 and Th17 proinflammatory phenotype [103,104], thus highlighting the role of the Th17 cell differentiation pathway in the immunopathogenesis of MS.”
BackgroundViral infections as potential triggers of type 1 diabetes
van der Werf, N., Kroese, F., Rozing, J., & Hillebrands, J. (2007) · Diabetes/Metabolism Research Reviews · doi:10.1002/dmrr.695 · Cited by 247 · see citing works
VirHostNet 2.0: surfing on the web of virus/host molecular interactions data
Guirimand, T., Delmotte, S., & Navratil, V. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1121 · Cited by 237 · see citing works
Infections and autoimmunity: the multifaceted relationship
Sfriso, P., Ghirardello, A., Botsios, C., Tonon, M., Zen, M., Bassi, N., Bassetto, F., & Doria, A. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0709517 · Cited by 233 · cited 1× · see citing works
“Similar to NDs, the pathogenesis of several autoimmune diseases has also been associated with several infectious agents, including viruses [140, 141].”
BackgroundInfectious Agents and Neurodegeneration
Chiara, G. D., Marcocci, M. E., Sgarbanti, R., Civitelli, L., Ripoli, C., Piacentini, R., Garaci, E., Grassi, C., & Palamara, A. T. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8320-7 · Cited by 231 · cited 1× · see citing works
“Aging causes alterations on the blood-brain barrier (BBB) and is also associated with increased oxidative stress in the brain, these age-mediated effects make the brain more permeable to viruses and neurons more vulnerable to viral insults [3].”
BackgroundGut inflammation and dysbiosis in human motor neuron disease
Rowin, J., Xia, Y., Jung, B., & Sun, J. (2017) · Physiological Reports · doi:10.14814/phy2.13443 · Cited by 224 · see citing works
Multiple sclerosis after infectious mononucleosis.
Nielsen, T., Rostgaard, K., Nielsen, N., Koch-Henriksen, N., Haahr, S., Sørensen, P., & Hjalgrim, H. (2007) · Archives of Neurology · doi:10.1001/archneur.64.1.72 · Cited by 221 · cited 1× · see citing works
“The viral infectious hypothesis of NDs is best supported in the case of MS as viral infections are the strongest environmental risk factor associated with its development, with Epstein– Barr virus (EBV) infection showing the strongest association [18, 28].”
BackgroundEpstein-Barr Virus in Systemic Autoimmune Diseases
Draborg, A., Duus, K., & Houen, G. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/535738 · Cited by 220 · see citing works
Kidney–brain crosstalk in the acute and chronic setting
Lu, R., Kiernan, M. C., Murray, A. M., Rosner, M. H., & Ronco, C. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.131 · Cited by 211 · see citing works
Herpes virus in Alzheimer's disease: relation to progression of the disease
Carbone, I., Lazzarotto, T., Ianni, M., Porcellini, E., Forti, P., Masliah, E., Gabrielli, L., & Licastro, F. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.024 · Cited by 208 · see citing works
Sanders, V., Felisan, S. L., Waddell, A. E., & Tourtellotte, W. (1996) · Journal of Neurovirology · doi:10.3109/13550289609146888 · Cited by 193 · see citing works
Timbury, M., & Edmond, E. (1979) · Journal of Clinical Pathology · doi:10.1136/jcp.32.9.859 · Cited by 191 · see citing works
Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer's disease patients
Wozniak, M. A., Shipley, S. J., Combrinck, M., Wilcock, G., & Itzhaki, R. (2005) · Journal of Medical Virology · doi:10.1002/jmv.20271 · Cited by 185 · cited 1× · see citing works
“Individuals seropositive to HSV-1 show increased risk of developing AD, and increased presence of HSV-1 was found in AD post-mortem brains, including in Aβ plaques, especially in apolipoprotein E4 gene carriers, a major susceptibility gene in sporadic AD [7, 39, 40].”
BackgroundEpstein-Barr Virus and Systemic Lupus Erythematosus
Draborg, A., Duus, K., & Houen, G. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/370516 · Cited by 182 · see citing works
Measles Virus Host Invasion and Pathogenesis
Laksono, B., de Vries, R. D., McQuaid, S., Duprex, W. P., & de Swart, R. D. (2016) · Viruses · doi:10.3390/v8080210 · Cited by 176 · see citing works
PHISTO: pathogen-host interaction search tool
Tekir, S. D., Çakır, T., Ardiç, E., Sayilirbas, A. S., Konuk, G., Konuk, M., Sariyer, H., Ugurlu, A., Karadeniz, I., Özgür, A., et al. (2013) · Bioinform. · doi:10.1093/bioinformatics/btt137 · Cited by 175 · cited 5× · see citing works
“STRING [74], PHISTO [75], VirusMentha [76] and HPIDB 3.”
MethodInfluentialAntigen Presentation and the Ubiquitin‐Proteasome System in Host–Pathogen Interactions
Loureiro, J., & Ploegh, H. L. (2006) · Advances in immunology · doi:10.1016/s0065-2776(06)92006-9 · Cited by 171 · cited 1× · see citing works
“Viruses are intracellular obligate parasites that lack their own replication machinery, thus to ensure their survival and reproduction they rely on the host, and via physical interactions they manipulate and exploit the host’s cellular machinery [44, 45].”
BackgroundRobinson, C. M., & Pfeiffer, J. K. (2014) · Annual Review of Virology · doi:10.1146/annurev-virology-031413-085550 · Cited by 163 · see citing works
VirusMentha: a new resource for virus-host protein interactions
Alberto, C., Licata, L., & Cesareni, G. (2014) · Nucleic Acids Res. · doi:10.1093/nar/gku830 · Cited by 161 · cited 2× · see citing works
“[111], PHISTO [80], VirusMentha [112] and HPIDB 3.0 [113].”
MethodInfluentialThe role of TDP-43 in amyotrophic lateral sclerosis and frontotemporal dementia
Mackenzie, I., & Rademakers, R. (2008) · Current Opinion in Neurology · doi:10.1097/wco.0b013e3283168d1d · Cited by 160 · cited 3× · see citing works
“We selected AD (DOID: 10652) , ALS (DOID:332), and PD (DOID:14330) to be compared to MS (DOID:2377) for the following reasons: (1) like MS, their development has also been associated with various viral infections, as indicated in Table 1, (2) similar to MS, they affect the CNS unlike other NDs that affect the peripher…”
BackgroundInfluentialTopological properties of protein interaction networks from a structural perspective
Gursoy, A., Keskin, O., & Nussinov, R. (2008) · Biochemical Society Transactions · doi:10.1042/bst0361398 · Cited by 156 · cited 2× · see citing works
“The most common properties used for the investigation of virus-host interactions are: node degree, degree centrality, betweenness centrality, shortest path and modularity score [62, 63, 67, 90, 91].”
BackgroundThe association between infectious burden and Parkinson's disease: A case-control study.
Bu, X.-L., Wang, X., Xiang, Y., Shen, L.-L., Wang, Q.-H., Liu, Y.-H., Jiao, S.-S., Wang, Y.-R., Cao, H.-Y., Yi, X., et al. (2015) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2015.05.015 · Cited by 153 · see citing works
Protein–Protein Interactions in Virus–Host Systems
Brito, A., & Pinney, J. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01557 · Cited by 145 · cited 1× · see citing works
“where the nodes represent the proteins and the edges their interactions [36].”
BackgroundRetroviruses and amyotrophic lateral sclerosis
Alfahad, T. B., & Nath, A. (2013) · Antiviral Research · doi:10.1016/j.antiviral.2013.05.006 · Cited by 144 · cited 2× · see citing works
“Amyotrophic Lateral Sclerosis HIV, HTLV-1, Human Endogenous Retrovirus K (HERVK), Enteroviruses (Poliovirus, Coxsackievirus, Echovirus, Enterovirus-A71 and Enterovirus-D68) [1,3,30,31]”
BackgroundViruses.STRING: A Virus-Host Protein-Protein Interaction Database
Cook, H., Doncheva, N., Szklarczyk, D., von Mering, C., & Jensen, L. (2018) · bioRxiv · doi:10.1101/396184 · Cited by 142
Lossius, A., Johansen, J., Torkildsen, Ø., Vartdal, F., & Holmøy, T. (2012) · Viruses · doi:10.3390/v4123701 · Cited by 141 · see citing works
ClusterViz: A Cytoscape APP for Cluster Analysis of Biological Network
Wang, J.-X., Zhong, J., Chen, G., Li, M., Wu, F.-X., & Pan, Y. (2015) · IEEE/ACM Transactions on Computational Biology & Bioinformatics · doi:10.1109/tcbb.2014.2361348 · Cited by 137 · cited 2× · see citing works
“The third step involves network topological analysis that can be performed with several plugins offered by Cytoscape such as NetworkAnalyzer [118] and CytoHubba [89], as well as clustering analysis apps , such as CytoCluster [119] and ClusterViz [120].”
MethodStructural principles within the human-virus protein-protein interaction network
Franzosa, E. A., & Xia, Y. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1101440108 · Cited by 132 · cited 1× · see citing works
“principles that govern PPIs of the host’s biological processes, the evolutionary trajectories of PPIs in the virus–host interaction network are antagonistic, as there is a constant competition between virus and host interactions where a change in a protein of the virus might result in a reciprocal counterchange in a h…”
BackgroundMicrobial Infection and Rheumatoid Arthritis
Li, S., Yu, Y.-S., Yue, Y.-S., Zhang, Z.-X., & Su, K. (2013) · Journal of Clinical & Cellular Immunology · doi:10.4172/2155-9899.1000174 · Cited by 132 · see citing works
Jarius, S., Eichhorn, P., Franciotta, D. M., Petereit, H.-F., Akman‐Demir, G., Wick, M. W., & Wildemann, B. (2016) · Journal of Neurology · doi:10.1007/s00415-016-8360-4 · Cited by 129 · see citing works
Cytokine determinants of viral tropism
McFadden, G., Mohamed, M. R., Rahman, M. M., & Bartee, E. (2009) · Nature reviews. Immunology · doi:10.1038/nri2623 · Cited by 128 · see citing works
CytoCluster: A Cytoscape Plugin for Cluster Analysis and Visualization of Biological Networks
Li, M., Li, D., Tang, Y., Wu, F.-X., & Wang, J.-X. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18091880 · Cited by 127 · cited 3× · see citing works
“The third step involves network topological analysis that can be performed with several plugins offered by Cytoscape such as NetworkAnalyzer [118] and CytoHubba [89], as well as clustering analysis apps , such as CytoCluster [119] and ClusterViz [120].”
MethodHost–pathogen protein interactions predicted by comparative modeling
Davis, F. P., Barkan, D. T., Eswar, N., McKerrow, J. H., & Šali, A. (2007) · Protein Science · doi:10.1110/ps.073228407 · Cited by 126 · cited 1× · see citing works
“For example, GO enrichment analysis can be performed to identify functional terms that are significantly targeted by pathogens in the three ontologies terms: biological process, molecular functions and cellular components [95].”
BackgroundRole of hypoxia-inducible factor-1α as a cancer therapy target
Patiar, S., & Harris, A. L. (2006) · Endocrine Related Cancer · doi:10.1677/erc.1.01290 · Cited by 121 · see citing works
The Interaction Between Human Papillomavirus and Other Viruses
Guidry, J. T., & Scott, R. S. (2016) · Virus Research · doi:10.1016/j.virusres.2016.11.002 · Cited by 121
Five years before multiple sclerosis onset: Phenotyping the prodrome
Wijnands, J. M. A., Zhu, F., Kingwell, E., Zhao, Y.-S., Ekuma, O., Lu, X., Evans, C., Fisk, J., Marrie, R., & Tremlett, H. (2018) · Multiple Sclerosis · doi:10.1177/1352458518783662 · Cited by 119 · see citing works
Gessain, A., & Mahieux, R. (2012) · Revue neurologique (Paris) · doi:10.1016/j.neurol.2011.12.006 · Cited by 119 · see citing works
Zhou, L., Saksena, M. M., & Saksena, N. K. (2013) · Virology Journal · doi:10.1186/1743-422x-10-172 · Cited by 119 · cited 1× · see citing works
“Several evidence indicates that neuroinflammation is involved in the progression of NDs, by directly or indirectly contributing to neuronal loss; however, whether the immune system participates in the initiation of these diseases remains undetermined [5, 46].”
BackgroundChen, C.-H., Lin, C.-L., & Kao, C. (2016) · PLoS ONE · doi:10.1371/journal.pone.0144589 · Cited by 115 · see citing works
Computational approaches for prediction of pathogen-host protein-protein interactions
Nourani, E., Khunjush, F., & Durmuş, S. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00094 · Cited by 115 · cited 1× · see citing works
“A current approach used to overcome this limitation is to use computationally predicted virus-host PPIs obtained from machine learning algorithms, but such methods are not without drawbacks due to the high false positive and false negative rates [109].”
MethodViruses as potential pathogenic agents in systemic lupus erythematosus
Nelson, P., Rylance, P., Roden, D., Trela, M., & Tugnet, N. (2014) · Lupus · doi:10.1177/0961203314531637 · Cited by 115 · see citing works
Ibrahim, A., Obeid, M. T., Jouma, M., Moasis, G. A., Al-Richane, W. L., Kindermann, I., Boehm, M., Roemer, K., Mueller-Lantzsch, N., & Gärtner, B. (2005) · Journal of Clinical Virology · doi:10.1016/j.jcv.2004.06.010 · Cited by 112 · see citing works
A systematic review of the incidence and prevalence of cancer in multiple sclerosis
Marrie, R., Reider, N., Cohen, J. A., Stüve, O., Trojano, M., Sørensen, P., Reingold, S., & Cutter, G. (2015) · Multiple Sclerosis · doi:10.1177/1352458514564489 · Cited by 110 · see citing works
Wicker, J., Whiteman, M. C., Beasley, D. W., Davis, C. T., Zhang, S.-L., Schneider, B. S., Higgs, S., Kinney, R., & Barrett, A. D. T. (2006) · Virology · doi:10.1016/j.virol.2006.03.007 · Cited by 110
Patrick, K. L., Bell, S. L., Weindel, C. G., & Watson, R. O. (2019) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00138 · Cited by 110 · cited 1× · see citing works
“however, how the interplay of these factors contributes to their development remains elusive [2].”
BackgroundViral Perturbations of Host Networks Reflect Disease Etiology
Gulbahce, N., Yan, H., Dricot, A., Padi, M., Byrdsong, D., Franchi, R., Lee, D., Rozenblatt–Rosen, O., Mar, J. C., Calderwood, M. A., et al. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002531 · Cited by 109 · cited 4× · see citing works
“Based on the local impact hypothesis, viral host targets of the associated virus are located in proximity of disease susceptibility genes within the network, and the expression pattern of such genes changes significantly [56, 65, 136].”
BackgroundInfluentialHepatitis C virus infection and type 1 and type 2 diabetes mellitus
Antonelli, A. (2014) · World Journal of Diabetes · doi:10.4239/wjd.v5.i5.586 · Cited by 108 · see citing works
Initial Immunopathogenesis of Multiple Sclerosis: Innate Immune Response
Hernández‐Pedro, N., Espinosa-Ramírez, G., de la Cruz, V. P., Pineda, B., & Sotelo, J. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/413465 · Cited by 108 · cited 1× · see citing works
“MS is a complex chronic immune-mediated demyelinating disease of the CNS, characterized by the presence of both white and grey mater lesions in the CNS, accompanied by immune cell infiltration of autoreactive T and B cells [130, 131].”
BackgroundThe role of viral infections in the development of autoimmune diseases
Hussein, H. M., & Rahal, E. A. (2019) · Critical reviews in microbiology · doi:10.1080/1040841x.2019.1614904 · Cited by 107 · cited 1× · see citing works
“Similar to NDs, the pathogenesis of several autoimmune diseases has also been associated with several infectious agents, including viruses [140, 141].”
BackgroundApolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review
Kuhlmann, I., Minihane, A. M., Huebbe, P., Nebel, A., & Rimbach, G. H. (2010) · Lipids in Health and Disease · doi:10.1186/1476-511x-9-8 · Cited by 106 · cited 1× · see citing works
“…Virus (EBV/HHV-4), Varicella-Zoster Virus (VZV/HHV-5), Human Herpesvirus 6 (HHV-6), Human Herpesvirus 7 (HHV-7), Hepatitis C Virus (HCV) [1,2,12 – 15] Multiple Sclerosis EBV, HHV-6, HSV-1, Measles Morbillivirus Virus, Rubella Virus, VZV, Human Endogenous Retrovirus W (HERV-W), Human T-cell…”
BackgroundChemokines and Chemokine Receptors in Multiple Sclerosis
Cheng, W., & Chen, G. (2014) · Mediators of Inflammation · doi:10.1155/2014/659206 · Cited by 106 · see citing works
Viral and Inflammatory Triggers of Neurodegenerative Diseases
Deleidi, M., & Ole Isacson, A. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003492 · Cited by 101 · cited 2× · see citing works
“it can eliminate acute viral infections or control chronic viral infections [42, 46].”
BackgroundA new reference implementation of the PSICQUIC web service
del-Toro, N., Dumousseau, M., Orchard, S., Jiménez, R., Galeota, E., Launay, G., Goll, J., Breuer, K., Ono, K., Salwínski, L., et al. (2013) · Nucleic Acids Res. · doi:10.1093/nar/gkt392 · Cited by 101 · cited 1×
“Virus–host and human intra-species PPI data can also be obtained from the PISCQUIC Web Service Client app in Cytoscape, an integration tool that provides data from multiple databases [83].”
MethodChen, M., Popescu, N., Woodworth, C., Berneman, Z., Corbellino, M., Lusso, P., Ablashi, D., & DiPaolo, J. (1994) · Journal of Virology · doi:10.1128/jvi.68.2.1173-1178.1994 · Cited by 98 · see citing works
Enteroviral Infection: The Forgotten Link to Amyotrophic Lateral Sclerosis?
Xue, Y. C., Feuer, R., Cashman, N. R., & Luo, H. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00063 · Cited by 97 · cited 3× · see citing works
“We selected AD (DOID: 10652) , ALS (DOID:332), and PD (DOID:14330) to be compared to MS (DOID:2377) for the following reasons: (1) like MS, their development has also been associated with various viral infections, as indicated in Table 1, (2) similar to MS, they affect the CNS unlike other NDs that affect the peripher…”
BackgroundInfluentialIdentifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains
Liu, Z.-P., Wang, Y., Zhang, X.-S., & Chen, L.-N. (2010) · BMC Systems Biology · doi:10.1186/1752-0509-4-s2-s11 · Cited by 96 · see citing works
Positive and Negative Regulation of Cellular Immune Responses in Physiologic Conditions and Diseases
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Adding to the Burden: Gastrointestinal Symptoms and Syndromes in Multiple Sclerosis
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The Ubiquitin-Conjugating System: Multiple Roles in Viral Replication and Infection
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“Viruses are intracellular obligate parasites that lack their own replication machinery, thus to ensure their survival and reproduction they rely on the host, and via physical interactions they manipulate and exploit the host’s cellular machinery [44, 45].”
BackgroundNavratil, V., de Chassey, B., Rabourdin‐Combe, C., & Lotteau, V. (2011) · BMC Systems Biology · doi:10.1186/1752-0509-5-13 · Cited by 84 · cited 3× · see citing works
“These molecular interactions can lead to the dysregulation of normal biological processes within the host, causing numerous diseases from cancer to NDs [54].”
BackgroundSinagra, E., Utzeri, E., Morreale, G. C., Fabbri, C., Pace, F., & Anderloni, A. A. (2020) · World Journal of Clinical Cases · doi:10.12998/wjcc.v8.i6.1013 · Cited by 82 · see citing works
An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes.
Levet, S., Medina, J., Joanou, J., Demolder, A., Queruel, N., Réant, K., Normand, M., Seffals, M., Dimier, J., Germi, R., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.94387 · Cited by 80 · see citing works
Evidence for Viral Etiology of Multiple Sclerosis
Tselis, A. (2011) · Seminars in neurology · doi:10.1055/s-0031-1287656 · Cited by 78 · cited 1× · see citing works
“The viral infectious hypothesis of NDs is best supported in the case of MS as viral infections are the strongest environmental risk factor associated with its development, with Epstein– Barr virus (EBV) infection showing the strongest association [18, 28].”
BackgroundMultiple Sclerosis and Cancer: The Ying-Yang Effect of Disease Modifying Therapies
Melamed, E., & Lee, M. W. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02954 · Cited by 77 · see citing works
Tekir, S. D., Çakır, T., & Ülgen, K. Ö. (2012) · Frontiers in Microbiology · doi:10.3389/fmicb.2012.00046 · Cited by 75 · cited 1× · see citing works
“degree, degree centrality, betweenness centrality, shortest path and modularity score [62, 63, 67, 90, 91].”
BackgroundCo-infection of Epstein-Barr virus and human papillomavirus in human tumorigenesis
Shi, Y., Peng, S., Yang, L.-F., Chen, X., Tao, Y.-G., & Cao, Y. (2016) · Chinese journal of cancer · doi:10.1186/s40880-016-0079-1 · Cited by 73 · see citing works
Irritable bowel syndrome correlates with increased risk of Parkinson’s disease in Taiwan
Lai, S., Liao, K., Lin, C.-L., & Sung, F. (2014) · European Journal of Epidemiology · doi:10.1007/s10654-014-9878-3 · Cited by 73 · see citing works
Th17 cells in autoimmune diseases
Han, L., Yang, J. C., Wang, X., Li, D., Lv, L., & Li, B. (2015) · Frontiers of Medicine · doi:10.1007/s11684-015-0388-9 · Cited by 73 · cited 1× · see citing works
“Th17 cells are also involved in the immunopathogenesis of multiple other autoimmune diseases including IBD and Rheumatoid arthritis [105].”
BackgroundHypoxia-inducible factor 1 and its role in viral carcinogenesis
Cuninghame, S., Jackson, R., & Zehbe, I. (2014) · Virology · doi:10.1016/j.virol.2014.02.027 · Cited by 72 · see citing works
Zecca, C., Riccitelli, G., Disanto, G., Singh, A., Digesu, G. A., Panicari, L., Puccini, F., Mattioli, M., Tubaro, A., & Gobbi, C. (2016) · European Journal of Neurology · doi:10.1111/ene.13010 · Cited by 69 · see citing works
Viral infections in the developing and mature brain.
van den Pol, A. N. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.06.002 · Cited by 68 · see citing works
Arleevskaya, M., Kravtsova, O., Lemerle, J., Renaudineau, Y., & Tsibulkin, A. P. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.01296 · Cited by 66 · see citing works
Infections and Systemic Lupus Erythematosus: Binding or Sparring Partners?
Rigante, D., & Esposito, S. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160817331 · Cited by 66 · see citing works
Possible Role of Human Herpesvirus 6 as a Trigger of Autoimmune Disease
Broccolo, F., Fusetti, L., & Ceccherini-Nelli, L. (2013) · TheScientificWorldJournal · doi:10.1155/2013/867389 · Cited by 64 · see citing works
HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact
Pinto, D. O., DeMarino, C., Pleet, M. L., Cowen, M., Branscome, H., Al Sharif, S., Jones, J., Dutartre, H., Lepene, B., Liotta, L. A., et al. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02147 · Cited by 64 · see citing works
Cytomegalovirus: a culprit or protector in multiple sclerosis?
Vanheusden, M., Stinissen, P., Hart, B. '. '., & Hellings, N. (2015) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2014.11.002 · Cited by 63 · see citing works
Durmuş, S., & Ülgen, K. Ö. (2016) · FEBS Open Bio · doi:10.1002/2211-5463.12167 · Cited by 63 · cited 1× · see citing works
“Comparative interactome analysis between DNA versus RNA viruses, revealed that the DNA viruses-human PPI network follows a scale free behavior, whereas the RNA viruseshuman PPI network does not follow a scale free behavior [58].”
BackgroundHIF-1alpha and infectious diseases: a new frontier for the development of new therapies
dos Santos, S. A., & de Andrade, D. R. (2017) · Revista do Instituto de Medicina Tropical de São Paulo · doi:10.1590/s1678-9946201759092 · Cited by 62 · cited 1× · see citing works
“signals during hypoxia, infection and the stimulation of pro-inflammatory signals [98].”
BackgroundZhang, X., & Markovic-Plese, S. (2010) · Clinical neurology and neurosurgery (Dutch-Flemish ed. Print) · doi:10.1016/j.clineuro.2010.04.020 · Cited by 61 · see citing works
The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis
Dolei, A. (2018) · Multiple Sclerosis · doi:10.1177/1352458517737370 · Cited by 58
Transient parkinsonism in West Nile virus encephalitis.
Robinson, R., Shahida, S., Madan, N., Rao, S.-M., & Khardori, N. (2003) · American Journal of Medicine · doi:10.1016/s0002-9343(03)00291-2 · Cited by 58 · cited 1× · see citing works
“In addition, infection with West Nile virus (WNV), a neurotropic virus of the Flaviviridae family that causes meningoencephalitis, can also result in the development of Parkinson-like symptoms that usually resolve over time [29, 30]; however, in some cases, the symptoms can persist, resulting in chronic PD [31].”
BackgroundThe commonality of protein interaction networks determined in neurodegenerative disorders (NDDs)
Limviphuvadh, V., Tanaka, S., Goto, S., Ueda, K., & Kanehisa, M. I. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btm307 · Cited by 57 · see citing works
Comorbidity and Health-Related Quality of Life in People with Multiple Sclerosis
Warren, S., Turpin, K., Pohar, S., Jones, C., & Warren, K. (2009) · International Journal of MS Care · doi:10.7224/1537-2073-11.1.6 · Cited by 56 · see citing works
HIV-associated motor neuron disease
Bowen, L. N., Tyagi, R., Li, W., Alfahad, T. B., Smith, B. R., Wright, M. E., Singer, E., & Nath, A. (2016) · Neurology · doi:10.1212/wnl.0000000000003258 · Cited by 55 · cited 1× · see citing works
“HIV, HTLV-1, Human Endogenous Retrovirus K (HERV-K), Enteroviruses (Poliovirus, Coxsackievirus, Echovirus, Enterovirus-A71 and Enterovirus-D68) [1,3,30,31] However, despite the association of viral infections with NDs, it is highly unlikely that viruses are solely responsible for the development…”
BackgroundRevisiting the Pathoetiology of Multiple Sclerosis: Has the Tail Been Wagging the Mouse?
Sen, M. K., Almuslehi, M. S. M., Shortland, P. J., Coorssen, J. R., & Mahns, D. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.572186 · Cited by 55 · cited 2× · see citing works
“The peripheral immune cells then lead to the destruction of oligodendrocytes and the release of myelin antigens causing the activation of resident microglia cells and the subsequent formation of autoreactive T cells [132, 133].”
BackgroundThe Role of Epstein–Barr Virus in Cervical Cancer: A Brief Update
Vranić, S., Cyprian, F., Akhtar, S., & Moustafa, A.-E. A. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00113 · Cited by 53
Multiple sclerosis disease progression: Contributions from a hypoxia–inflammation cycle
Yang, R., & Dunn, J. F. (2018) · Multiple Sclerosis Journal · doi:10.1177/1352458518791683 · Cited by 52 · see citing works
Current mechanistic insights into the role of infection in systemic lupus erythematosus.
Pan, Q., Liu, Z.-J., Liao, S., Ye, L., Lu, X., Chen, X.-Q., Li, Z.-H., Li, X., Xu, Y.-Z., & Liu, H.-F. (2019) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2019.109122 · Cited by 51
Association of herpesvirus infection with the development of genital cancer
Koffa, M., Koumantakis, E., Ergazaki, M., Tsatsanis, C., & Spandidos, D. (1995) · International Journal of Cancer · doi:10.1002/ijc.2910630112 · Cited by 49
Viruses and Interactomes in Translation
Meyniel‐Schicklin, L., de Chassey, B., André, P., & Lotteau, V. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.014738 · Cited by 48 · cited 2× · see citing works
“Viruses through the evolutionary processes have evolved strategies that allow them to efficiently adapt to the scale-free nature of the human interactome and via targeted attacks interact with essential proteins (hubs, bottlenecks) that are highly connected, allowing them to influence multiple functions and pathways s…”
BackgroundPathoetiology of multiple sclerosis: are we barking up the wrong tree?
Stys, P. K. (2013) · F1000Prime Reports · doi:10.12703/p5-20 · Cited by 46 · cited 2× · see citing works
“The peripheral immune cells then lead to the destruction of oligodendrocytes and the release of myelin antigens causing the activation of resident microglia cells and the subsequent formation of autoreactive T cells [132, 133].”
BackgroundSa, A. C. C., Madsen, H., & Brown, J. R. (2019) · Scientific Reports · doi:10.1038/s41598-019-45129-8 · Cited by 46 · cited 1× · see citing works
“[114] has investigated the mechanisms of viral-induced pathogenesis in NDs, but at the transcriptomic level by comparing the gene expression profiles of AD or PD patients with three viral infection datasets and was able to identify shared pathways between these NDs and viruses.”
BackgroundHealth and elite sport : is high performance sport a healthy pursuit?
Baker, J., Safai, P., & Fraser-Thomas, J. (2014) · doi:10.4324/9781315885919 · Cited by 46
A role for viral infections in Parkinson’s etiology?
Olsen, L. K., Dowd, E., & McKernan, D. P. (2018) · Neuronal Signaling · doi:10.1042/ns20170166 · Cited by 46 · see citing works
PROGRESS IN COMPUTATIONAL STUDIES OF HOST–PATHOGEN INTERACTIONS
Zhou, H., Jin, J., & Wong, L. (2012) · Journal of Bioinformatics and Computational Biology · doi:10.1142/s0219720012300018 · Cited by 46 · cited 1× · see citing works
“host’s immune system and cellular processes [94].”
Computational analysis of protein interaction networks for infectious diseases
Pan, A., Lahiri, C., Rajendiran, A., & Shanmugham, B. (2015) · Briefings in Bioinformatics · doi:10.1093/bib/bbv059 · Cited by 45 · cited 1× · see citing works
“There are several reviews that have extensively described databases and tools that can be implemented to investigate these central steps [71, 72] .”
BackgroundAdaptive immune response to viral infections in the central nervous system
Libbey, J., & Fujinami, R. (2014) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-53488-0.00010-9 · Cited by 41 · see citing works
Liver involvement in adults with measles.
Dinh, A., Fleuret, V., & Hanslik, T. (2013) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2013.06.014 · Cited by 40
Reeves, M., Coleman, H., Chadderton, J., Goddard, M., Sissons, J. G. P., & Sinclair, J. (2004) · Journal of General Virology · doi:10.1099/vir.0.80285-0 · Cited by 39
An Effective Method to Identify Shared Pathways and Common Factors among Neurodegenerative Diseases
Li, P., Nie, Y.-L., & Yu, J.-K. (2015) · PLoS ONE · doi:10.1371/journal.pone.0143045 · Cited by 38 · cited 1× · see citing works
“…a group of NDs have primarily concentrated in identifying common molecular mechanisms by identifying direct protein/genes commonalities and pathways among NDs and indirect network relationships between NDs via topological association by identifying common modules in these diseases [69 – 72].”
BackgroundThe Role of Viruses and of APOE in Dementia
Itzhaki, R., Dobson, C., Shipley, S. J., & Wozniak, M. A. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1297.003 · Cited by 38 · cited 1× · see citing works
“Individuals seropositive to HSV-1 show increased risk of developing AD, and increased presence of HSV-1 was found in AD post-mortem brains, including in Aβ plaques, especially in apolipoprotein E4 gene carriers, a major susceptibility gene in sporadic AD [7, 39, 40].”
BackgroundHTLV-1 induced molecular mimicry in neurological disease.
Lee, S.-M., Morcos, Y., Jang, H., Stuart, J., & Levin, M. (2005) · Current Topics in Microbiology and Immunology · doi:10.1007/3-540-30791-5_7 · Cited by 36
Update on rheumatic manifestations of infectious diseases
Becker, J., & Winthrop, K. (2010) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e328333b9f5 · Cited by 35 · cited 1× · see citing works
“In addition, the KEGG enrichment results indicates that 42.4% of the pathways belong to the Rheumatoid arthritis group, suggesting the existence of common pathogenic mechanisms between MS and Rheumatoid arthritis [100 – 102].”
BackgroundInfluentialViral Organization of Human Proteins
Wuchty, S., Siwo, G., & Ferdig, M. (2008) · PLoS ONE · doi:10.1371/journal.pone.0011796 · Cited by 35 · cited 1×
“Viral proteins have a preference to target human proteins that are hubs, have high betweenness (bottlenecks), are articulation points and belong to rich clubs [42 – 45].”
BackgroundVasaikar, S., Padhi, A. K., Jayaram, B., & Gomes, J. (2013) · BMC Neuroscience · doi:10.1186/1471-2202-14-3 · Cited by 33 · cited 1× · see citing works
“NDs and also allows the reconstruction and analysis of these NDs networks using PPI, regulatory and Boolean networks; however, it was last updated in 2016 [129].”
MethodIntegrative analysis of Multiple Sclerosis using a systems biology approach
Cervantes-Gracia, K., & Husi, H. (2018) · Scientific Reports · doi:10.1038/s41598-018-24032-8 · Cited by 32 · see citing works
Enteroviral Infection Leads to Transactive Response DNA-Binding Protein 43 Pathology in Vivo
Xue, Y. C., Ruller, C. M., Fung, G., Mohamud, Y., Deng, H., Liu, H., Zhang, J., Feuer, R., & Luo, H. (2018) · American Journal Of Pathology · doi:10.1016/j.ajpath.2018.08.013 · Cited by 31 · cited 3× · see citing works
“We selected AD (DOID: 10652) , ALS (DOID:332), and PD (DOID:14330) to be compared to MS (DOID:2377) for the following reasons: (1) like MS, their development has also been associated with various viral infections, as indicated in Table 1, (2) similar to MS, they affect the CNS unlike other NDs that affect the peripher…”
BackgroundInfluentialHamaue, N., Ogata, A., Terado, M., Ohno, K., Kikuchi, S., Sasaki, H., Tashiro, K., Hirafuji, M., & Minami, M. (2006) · Neurochemical Research · doi:10.1007/s11064-006-9197-5 · Cited by 29 · cited 1× · see citing works
“Similar to WNV, parkinsonian-like symptoms can also be caused by other viruses of the Flaviviridae family [21, 32], including Japanese encephalitis virus [33] and Saint Louis encephalitis virus [34].”
BackgroundImplications of progressive multifocal leukoencephalopathy and JC virus for the etiology of MS
Stoner, G. (1991) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1991.tb03954.x · Cited by 29 · see citing works
The aliens inside human DNA: HERV-W/MSRV/syncytin-1 endogenous retroviruses and neurodegeneration.
Dolei, A., Uleri, E., Ibba, G., Caocci, M., Piu, C., & Serra, C. (2015) · Journal of Infection in Developing Countries · doi:10.3855/jidc.6916 · Cited by 28 · see citing works
Neurotropic viruses and Alzheimer disease
Lin, W.-R., Shang, D., & Itzhaki, R. (1996) · Molecular and Chemical Neuropathology · doi:10.1007/bf02815215 · Cited by 28 · cited 1× · see citing works
“Individuals seropositive to HSV-1 show increased risk of developing AD, and increased presence of HSV-1 was found in AD post-mortem brains, including in Aβ plaques, especially in apolipoprotein E4 gene carriers, a major susceptibility gene in sporadic AD [7, 39, 40].”
BackgroundPathwayConnector: finding complementary pathways to enhance functional analysis
Minadakis, G., Zachariou, M., Oulas, A., & Spyrou, G. (2018) · Bioinform. · doi:10.1093/bioinformatics/bty693 · Cited by 27 · cited 2×
“The enriched KEGG pathway results obtained from the 17 common ND proteins were then entered into the PathwayConnector web tool [108] to discover a complementary network of pathways that interact with the common ND pathways (Figure 6).”
MethodSelf-citationWest Nile virus infection presenting as cerebellar ataxia and fever: case report.
Kanagarajan, K., Ganesh, S., Alakhras, M., Go, E., Recco, R., & Zaman, M. (2003) · Southern medical journal (Birmingham, Ala. Print) · doi:10.1097/01.smj.0000054912.04257.dc · Cited by 26 · cited 1×
“In addition, infection with West Nile virus (WNV), a neurotropic virus of the Flaviviridae family that causes meningoencephalitis, can also result in the development of Parkinson-like symptoms that usually resolve over time [29, 30]; however, in some cases, the symptoms can persist, resulting in chronic PD [31].”
BackgroundKalathur, R., Pinto, J. P., Sahoo, B., Chaurasia, G., & Futschik, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-05224-0 · Cited by 24 · see citing works
Potential role of viruses in neurodegeneration
Kristensson, K. (1992) · Molecular and Chemical Neuropathology · doi:10.1007/bf03159960 · Cited by 24 · cited 1× · see citing works
“Infection by certain neurotropic viruses can also lead to the formation of neuropathological and/or immunopathological lesions with the pattern of the resulting lesions having similar distribution as that of the common NDs [48, 49].”
BackgroundVirus interactions with human signal transduction pathways
Zhao, Z., Xia, J., Taştan, Ö., Singh, I., Kshirsagar, M., Carbonell, J. R., & Klein‐Seetharaman, J. (2011) · International Journal of Computational Biology and Drug Design · doi:10.1504/ijcbdd.2011.038658 · Cited by 23 · cited 1× · see citing works
“On the other hand, GO and pathway enrichment analysis has been used in several studies to identify common and unique infection strategies, as well as pathogen-mediated pathogenic mechanisms that may lead to disease [39,44,55 – 57].”
Method
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Cited by
Sorted by citations
Proteomes Are of Proteoforms: Embracing the Complexity
Carbonara, K., Andonovski, M., & Coorssen, J. (2021) · Proteomes · doi:10.3390/proteomes9030038 · Cited by 87 · see citing works
Onisiforou, A., Charalambous, E. G., & Zanos, P. (2025) · Microorganisms · doi:10.3390/microorganisms13010090 · Cited by 31 · see citing works
“These evolutionary adaptations enable viruses to modulate host pathways via virus–host PPIs, influencing disease-associated mechanisms and potentially contributing to NDs, including AD [33,131].”
Self-citationOnisiforou, A., & Zanos, P. (2023) · bioRxiv · doi:10.1093/infdis/jiae242 · Cited by 27 · see citing works
“…a high degree of neurotropism; (2) viruses that cause hepatitis (HCV and HBV), which target the liver and can lead to various degrees of liver damage and inflammation; and (3) respiratory viruses (SARS-CoV-2 and IAV), which primarily target the respiratory tract and cause respiratory illness.”
BackgroundSelf-citationOnisiforou, A., & Spyrou, G. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.843128 · Cited by 27 · see citing works
“(ii) Collection of NDs disease-associated data Using the same approach as in our previous work (36), we obtained disease-associated gene data for each of the four NDs (ALS, AD, PD and MS) using the STRING: disease query of the”
MethodInfluentialSelf-citationNeurotropic virus infection and neurodegenerative diseases: Potential roles of autophagy pathway
Zhao, Y., Xu, K., Shu, F., & Zhang, F. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14548 · Cited by 20 · see citing works
Onisiforou, A., & Spyrou, G. M. (2022) · Viruses · doi:10.3390/v14102270 · Cited by 19 · see citing works
“One important limitation of our study, is that non-statistically significant GO biological processes could also be important, as SARS-CoV-2 might exert disease effects through them [23].”
BackgroundMethodInfluentialSelf-citationOnisiforou, A., & Zanos, P. (2024) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2024.10.011 · Cited by 15 · see citing works
“Consequently these hubs act as key “ comorbidity disease communicator nodes ” in the network [45].”
BackgroundMethodSelf-citationMolecular signatures of premature aging in Major Depression and Substance Use Disorders
Onisiforou, A., Zanos, P., & Georgiou, P. (2024) · Scientific Data · doi:10.1038/s41597-024-03538-z · Cited by 17 · see citing works
Self-citationWang, X., Luo, J.-Y., Cai, X.-Y., Liu, R.-B., Li, Y.-X., & Hon, C. (2025) · Biosafety and Health · doi:10.1016/j.bsheal.2025.07.005 · Cited by 11 · see citing works
Fongsaran, C., Jirakanwisal, K., Peng, B.-H., Fracassi, A., Taglialatela, G., Dineley, K. T., Paessler, S., & Cisneros, I. E. (2024) · Brain, Behavior, & Immunity - Health · doi:10.1016/j.bbih.2024.100780 · Cited by 9 · see citing works
“Evidence suggests infections with neurotropic pathogens, including alphaviruses, contribute to the development of neurodegenerative diseases (Onisiforou and Spyrou, 2021).”
BackgroundEnterovirus infection and its relationship with neurodegenerative diseases
Junior, I. P. D. S., & Vieira, T. C. R. G. (2023) · Memórias do Instituto Oswaldo Cruz · doi:10.1590/0074-02760220252 · Cited by 8 · see citing works
Georgiou, A. N., Zanos, P., & Onisiforou, A. (2026) · Communications Medicine · doi:10.1038/s43856-026-01471-3 · Cited by 6 · see citing works
Self-citationUnderestimated virus impaired cognition-more evidence and more work to do
Awan, M. U. N., Mahmood, F., Peng, X.-B., Zheng, F., & Xu, J. L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1550179 · Cited by 3 · see citing works
Peng, S., Ouyang, J., Liu, Y., Wang, L., & Liu, R. (2025) · Medicine · doi:10.1097/md.0000000000044145 · Cited by 2 · see citing works
Georgiou, A. N., Zanos, P., & Onisiforou, A. (2025) · bioRxiv · doi:10.1101/2025.03.14.643306 · Cited by 2 · see citing works
Self-citationChen, H., Liu, J.-X., Liu, D., Hao, G.-F., & Yang, G.-F. (2024) · Reviews in Medical Virology · doi:10.1002/rmv.2517 · Cited by 2 · see citing works
Onisiforou, A. (2026) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofag097 · Cited by 1 · see citing works
“Together, these mechanistic insights support both the outside-in hypothesis, in which peripheral EBV-driven immune dysregulation triggers CNS autoimmunity, and the inside-out hypothesis, in which primary CNS injury may expose novel antigens that fuel EBV-driven autoreactivity [41, 43].”
Self-citationAltas, B., Georgiou, P., Onisiforou, M., Zanos, P., & Onisiforou, A. (2025) · bioRxiv · doi:10.1101/2025.11.03.686445 · Cited by 1 · see citing works
“Over the course of evolution, viruses have acquired diverse strategies to evade host immunity, such as disrupting antigen presentation pathways and imitating host immune functions 18,68 .”
InfluentialSelf-citationChatterjee, A., Dey, S., Ghosh, H., & Dasgupta, S. (2025) · Gene Reports · doi:10.1016/j.genrep.2025.102255 · Cited by 1 · see citing works
Harnessing nature – plant compunds as potential breakthrough therapeutics for Parkinon’s Disease
Cytlau, B., Lach, A., Skorupa, M., & Marczyk, Ł. (2024) · Journal of Pre-Clinical and Clinical Research · doi:10.26444/jpccr/192629
Onisiforou, A., & Zanos, P. (2024) · bioRxiv · doi:10.1101/2024.06.25.600630
Self-citation
- Authors
- Onisiforou, A., & Spyrou, G. M.
- Affiliations
- The Cyprus Institute of Neurology & Genetics - Postgraduate Education (CY)
- Corresponding author
- Spyrou, George M
- Venue
- Briefings in Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-05-10
- Volume
- 22
- Issue
- 6
- ISSN
- 1467-5463 (ISSN-L)
- 1477-4054
- PMC
- PMC8574625
- OpenAlex
- W3163530683
- Cited by
- 23
- References
- 246
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 6 · 2023: 2 · 2022: 3 · 2021: 1
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Briefings in Bioinformatics (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Telethon Foundation
- Holland Research School of Molecular Chemistry
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- neurodegenerative diseases, multiple sclerosis, disease networks, network centrality, KEGG pathways, Th17 cell differentiation, immune system process, therapeutic target, viral proteins
- MeSH terms
- Humans, Models, Biological, Multiple Sclerosis, Viruses, Virus Physiological Phenomena, Host-Pathogen Interactions, Protein Interaction Maps, Gene Ontology
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