{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:02:42Z","timestamp":1760238162034,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012854","name":"Children's Hospital Research Institute of Manitoba","doi-asserted-by":"publisher","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}],"id":[{"id":"10.13039\/100012854","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The zika virus (ZIKV) is a neurotropic virus that causes congenital abnormalities in babies when they are infected in utero. Some studies have reported these congenital abnormalities result from ZIKV attacking neural progenitor cells within the brain which differentiate into neurons, oligodendrocytes, and astrocytes. Each of these glial cells play important roles during development of the fetal brain. In addition to ZIKV-induced congenital abnormalities, infected patients experience gastrointestinal complications. There are presently no reports investigating the role of this virus at the proteomic level in gastrointestinal associated cells, so we conducted an in vitro proteomic study of ZIKV-induced changes in Caco-2, a colon-derived human cell line which is known to be permissive to ZIKV infection. We used SomaScan, a new aptamer-based proteomic tool to identify host proteins that are dysregulated during ZIKV infection at 12, 24, and 48 h post-infection. Bioinformatic analyses predicted that dysregulation of differentially-regulated host proteins results in various gastrointestinal diseases. Validation of the clinical relevance of these promising protein targets will add to the existing knowledge of ZIKV biology. These potential proteins may be useful targets towards the development of therapeutic interventions.<\/jats:p>","DOI":"10.3390\/v12070771","type":"journal-article","created":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T10:22:02Z","timestamp":1594981322000},"page":"771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["ZIKV Infection Induces DNA Damage Response and Alters the Proteome of Gastrointestinal Cells"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7442-0102","authenticated-orcid":false,"given":"Kathleen","family":"Glover","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Manitoba Centre for Proteomics &amp; Systems Biology, Room 799, University of Manitoba, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin M.","family":"Coombs","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Manitoba Centre for Proteomics &amp; Systems Biology, Room 799, University of Manitoba, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada"},{"name":"Children\u2019s Hospital Research Institute of Manitoba, Room 513, John Buhler Research Centre, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/S0140-6736(16)00562-6","article-title":"Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study","volume":"387","author":"Blake","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/S1473-3099(17)30727-2","article-title":"Association between microcephaly, Zika virus infection, and other risk factors in Brazil: Final report of a case-control study","volume":"18","author":"Ximenes","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","unstructured":"WHO (2020, May 06). Countries and Territories with Current or Previous Zika Virus Transmission. Available online: https:\/\/www.who.int\/emergencies\/diseases\/zika\/countries-with-zika-and-vectors-table.pdf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13756-016-0112-9","article-title":"The 2014\u20132015 Ebola outbreak in West Africa: Hands on","volume":"5","author":"Vetter","year":"2016","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_5","unstructured":"WHO (2020, May 06). Region of the Americas\/Pan American Health Organization. Available online: http:\/\/www.paho.org\/data\/index.php\/en\/mnu-topics\/zika\/524-zika-weekly-en.htm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1056\/NEJMoa0805715","article-title":"Zika virus outbreak on Yap Island, Federated States of Micronesia","volume":"360","author":"Duffy","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"523","DOI":"10.4103\/2249-4863.197256","article-title":"Zika virus: An overview","volume":"5","author":"Rawal","year":"2016","journal-title":"J. Fam. Med. Prim. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.eimc.2016.02.012","article-title":"First case of imported Zika virus infection in Spain","volume":"34","author":"Gonzalez","year":"2016","journal-title":"Enferm. Infec. Micr. Clin."},{"key":"ref_9","first-page":"211","article-title":"Technical guidelines for the prevention, diagnosis and treatment of Zika virus infection","volume":"54","year":"2016","journal-title":"Rev. Med. Inst. Mex. Seguro Soc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e12164","DOI":"10.1111\/jspn.12164","article-title":"Understanding Zika virus","volume":"22","author":"Murray","year":"2017","journal-title":"J. Spec. Pediatr. Nurs."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jiph.2019.07.006","article-title":"Clinical relevance of Zika symptoms in the context of a Zika Dengue epidemic","volume":"13","author":"Garcell","year":"2020","journal-title":"J. Infect. Public Health"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Verhoeckx, K., Cotter, P., L\u00f3pez-Exp\u00f3sito, I., Kleiveland, C., Lea, T., Mackie, A., Requena, T., Swiatecka, D., and Wichers, H. (2015). Caco-2 cell line. The Impact of Food Bioactives on Health: In Vitro and Ex Vivo Models, Springer.","DOI":"10.1007\/978-3-319-16104-4"},{"key":"ref_13","first-page":"78","article-title":"Zika virus infection in a pediatric patient with acute gastrointestinal involvement","volume":"9","author":"Slavov","year":"2017","journal-title":"Pediatric Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e93","DOI":"10.1038\/emi.2016.99","article-title":"Differential cell line susceptibility to the emerging Zika virus: Implications for disease pathogenesis, non-vector-borne human transmission and animal reservoirs","volume":"5","author":"Chan","year":"2016","journal-title":"Emerg. Microbes Infect."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1800309","DOI":"10.1002\/pmic.201800309","article-title":"Vero cell proteomic changes induced by Zika virus infection","volume":"19","author":"Glover","year":"2019","journal-title":"Proteomics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"596","DOI":"10.3389\/fmicb.2019.00596","article-title":"Zika virus infection disrupts astrocytic proteins involved in synapse control and axon guidance","volume":"10","author":"Sher","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Rashid, M.U., Zahedi-Amiri, A., Glover, K.K.M., Ang, G., Nickol, M.E., Kindrachuk, J., Wilkins, J.A., and Coombs, K.M. (2019). Zika virus dysregulates human Sertoli cell proteins involved in spermatogenesis with little effect on blood-testes tight junctions. PLoS Neg. Trop. Dis., 24.","DOI":"10.1371\/journal.pntd.0008335"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/j.1600-065X.2009.00782.x","article-title":"Molecular mechanism and function of CD40\/CD40L engagement in the immune system","volume":"229","author":"Elgueta","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1042\/BJ20100323","article-title":"Mechanisms and functions of p38 MAPK signalling","volume":"429","author":"Cuadrado","year":"2010","journal-title":"Biochem. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.1242\/dev.101071","article-title":"Chemokine signaling in development and disease","volume":"141","author":"Wang","year":"2014","journal-title":"Development"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/embj.201488027","article-title":"Dendritic cell maturation: Functional specialization through signaling specificity and transcriptional programming","volume":"33","author":"Dalod","year":"2014","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2016.05.001","article-title":"STAT3 signaling in immunity","volume":"31","author":"Hillmer","year":"2016","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1073\/pnas.0511148103","article-title":"Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins","volume":"103","author":"Gaspar","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1016\/j.dnarep.2009.04.016","article-title":"Viral manipulation of DNA repair and cell cycle checkpoints","volume":"8","author":"Chaurushiya","year":"2009","journal-title":"DNA Repair"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1080\/00207454.2016.1212854","article-title":"Neuroinflammation pathways: A general review","volume":"127","author":"Shabab","year":"2017","journal-title":"Int. J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17044","DOI":"10.1038\/celldisc.2017.44","article-title":"A role for ErbB signaling in the induction of reactive astrogliosis","volume":"3","author":"Chen","year":"2017","journal-title":"Cell Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12943-017-0611-1","article-title":"Cdk5 links with DNA damage response and cancer","volume":"16","author":"Liu","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e00638-19","DOI":"10.1128\/JVI.00638-19","article-title":"Zika virus infection induces DNA damage response in human neural progenitors that enhances viral replication","volume":"93","author":"Hammack","year":"2019","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1021\/acs.jproteome.5b00196","article-title":"Highly pathogenic H5N1 and novel H7N9 influenza A viruses induce more profound proteomic host responses than seasonal and pandemic H1N1 strains","volume":"14","author":"Simon","year":"2015","journal-title":"J. Proteome Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/35044005","article-title":"The DNA damage response: Putting checkpoints in perspective","volume":"408","author":"Zhou","year":"2000","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1101\/gad.914401","article-title":"Cell cycle checkpoint signaling through the ATM and ATR kinases","volume":"15","author":"Abraham","year":"2001","journal-title":"Genes Dev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature03097","article-title":"Cell-cycle checkpoints and cancer","volume":"432","author":"Kastan","year":"2004","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA damage response: Making it safe to play with knives","volume":"40","author":"Ciccia","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"254","DOI":"10.3389\/fnagi.2016.00254","article-title":"c-Abl inhibitors enable insights into the pathophysiology and neuroprotection in Parkinson\u2019s Disease","volume":"8","author":"Lindholm","year":"2016","journal-title":"Front. Aging Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13007","DOI":"10.1128\/JVI.79.20.13007-13017.2005","article-title":"Induction and utilization of an ATM signaling pathway by polyomavirus","volume":"79","author":"Dahl","year":"2005","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5844","DOI":"10.1073\/pnas.0501916102","article-title":"DNA repair proteins affect the lifecycle of herpes simplex virus 1","volume":"102","author":"Lilley","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8156","DOI":"10.1074\/jbc.M411405200","article-title":"Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment","volume":"280","author":"Kudoh","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"30336","DOI":"10.1074\/jbc.M500976200","article-title":"Activation of ataxia telangiectasia-mutated DNA damage checkpoint signal transduction elicited by herpes simplex virus infection","volume":"280","author":"Shirata","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5316","DOI":"10.1128\/JVI.02677-07","article-title":"Ataxia telangiectasia-mutated damage-signaling kinase- and proteasome-dependent destruction of Mre11-Rad50-Nbs1 Subunits in simian virus 40-infected primate cells","volume":"82","author":"Zhao","year":"2008","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/35096019","article-title":"A decade of CDK5","volume":"2","author":"Dhavan","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/ncb1829","article-title":"Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death","volume":"11","author":"Tian","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/ncb2058","article-title":"The role of Cdk5-mediated apurinic\/apyrimidinic endonuclease 1 phosphorylation in neuronal death","volume":"12","author":"Huang","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9630","DOI":"10.1128\/JVI.01095-09","article-title":"Genetic and pharmacologic alteration of cathepsin expression influences reovirus pathogenesis","volume":"83","author":"Johnson","year":"2009","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9919","DOI":"10.1128\/JVI.00388-12","article-title":"Hepatitis C virus-mediated inhibition of cathepsin S increases invariant-chain expression on hepatocyte surface","volume":"86","author":"Kim","year":"2012","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"642","DOI":"10.3389\/fphar.2019.00642","article-title":"Transcriptome profiling reveals pro-inflammatory cytokines and matrix metalloproteinase activation in Zika virus infected human umbilical vein endothelial cells","volume":"10","author":"Khaiboullina","year":"2019","journal-title":"Front. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1161\/STROKEAHA.109.561951","article-title":"Sonic hedgehog regulates ischemia\/hypoxia-induced neural progenitor proliferation","volume":"40","author":"Sims","year":"2009","journal-title":"Stroke"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.chom.2010.10.006","article-title":"Dengue virus-induced autophagy regulates lipid metabolism","volume":"8","author":"Heaton","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_48","first-page":"282041","article-title":"Lipophagy: Connecting autophagy and lipid metabolism","volume":"2102","author":"Singh","year":"2012","journal-title":"Int. J. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1017\/erm.2015.19","article-title":"Apoptosis, autophagy and unfolded protein response pathways in Arbovirus replication and pathogenesis","volume":"18","author":"Iranpour","year":"2016","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.chom.2018.05.005","article-title":"Flaviviruses exploit the lipid droplet protein AUP1 to trigger lipophagy and drive virus production","volume":"23","author":"Zhang","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13648","DOI":"10.1074\/jbc.M807498200","article-title":"Inhibition of sphingosine kinase by bovine viral diarrhea virus NS3 is crucial for efficient viral replication and cytopathogenesis","volume":"284","author":"Yamane","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Seo, Y.J., Pritzl, C.J., Vijayan, M., Bomb, K., McClain, M.E., Alexander, S., and Hahm, B. (2013). Sphingosine kinase 1 serves as a pro-viral factor by regulating viral RNA synthesis and nuclear export of viral ribonucleoprotein complex upon influenza virus infection. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075005"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.virol.2013.11.039","article-title":"Sphingosine kinase 1 regulates measles virus replication","volume":"450","author":"Vijayan","year":"2014","journal-title":"Virology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4291\/wjgp.v7.i1.27","article-title":"Current application of proteomics in biomarker discovery for inflammatory bowel disease","volume":"15","author":"Chan","year":"2016","journal-title":"World J. Gastrointest. Pathophysiol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/7\/771\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:49:17Z","timestamp":1760176157000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/7\/771"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,17]]},"references-count":54,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["v12070771"],"URL":"https:\/\/doi.org\/10.3390\/v12070771","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2020,7,17]]}}}