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High-resolution computational modeling of immune responses in the gut

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dc.contributor.authorVerma, Meghnaen
dc.contributor.authorBassaganya-Riera, Josepen
dc.contributor.authorLeber, Andrewen
dc.contributor.authorTubau-Juni, Nuriaen
dc.contributor.authorHoops, Stefanen
dc.contributor.authorAbedi, Vidaen
dc.contributor.authorChen, Xien
dc.contributor.authorHontecillas, Raquelen
dc.date.accessioned2021-10-14T18:46:03Zen
dc.date.available2021-10-14T18:46:03Zen
dc.date.issued2019-06-01en
dc.date.updated2021-10-14T18:45:58Zen
dc.description.abstractBackground: Helicobacter pylori causes gastric cancer in 1-2% of cases but is also beneficial for protection against allergies and gastroesophageal diseases. An estimated 85% of H. pylori-colonized individuals experience no detrimental effects. To study the mechanisms promoting host tolerance to the bacterium in the gastrointestinal mucosa and systemic regulatory effects, we investigated the dynamics of immunoregulatory mechanisms triggered by H. pylori using a high-performance computing-driven ENteric Immunity SImulator multiscale model. Immune responses were simulated by integrating an agent-based model, ordinary, and partial differential equations. Results: The outputs were analyzed using 2 sequential stages: The first used a partial rank correlation coefficient regression-based and the second a metamodel-based global sensitivity analysis. The influential parameters screened from the first stage were selected to be varied for the second stage. The outputs from both stages were combined as a training dataset to build a spatiotemporal metamodel. The Sobol indices measured time-varying impact of input parameters during initiation, peak, and chronic phases of infection. The study identified epithelial cell proliferation and epithelial cell death as key parameters that control infection outcomes. In silico validation showed that colonization with H. pylori decreased with a decrease in epithelial cell proliferation, which was linked to regulatory macrophages and tolerogenic dendritic cells. Conclusions: The hybrid model of H. pylori infection identified epithelial cell proliferation as a key factor for successful colonization of the gastric niche and highlighted the role of tolerogenic dendritic cells and regulatory macrophages in modulating the host responses and shaping infection outcomes.en
dc.description.versionPublished versionen
dc.format.extent18 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN giz062 (Article number)en
dc.identifier.doihttps://doi.org/10.1093/gigascience/giz062en
dc.identifier.eissn2047-217Xen
dc.identifier.issn2047-217Xen
dc.identifier.issue6en
dc.identifier.orcidHontecillas-Magarzo, Raquel [0000-0003-2942-6294]en
dc.identifier.orcidChen, Xi [0000-0001-7965-9198]en
dc.identifier.other5513894 (PII)en
dc.identifier.pmid31185494en
dc.identifier.urihttp://hdl.handle.net/10919/105389en
dc.identifier.volume8en
dc.language.isoenen
dc.publisherOxford University Pressen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000475755000008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectBiologyen
dc.subjectagent-based modelen
dc.subjectordinary differential equationen
dc.subjectGaussian processen
dc.subjectHelicobacter pylorien
dc.subjecthigh-performance computingen
dc.subjectmetamodelen
dc.subjectsensitivity analysisen
dc.subjectimmune systemen
dc.subjectdendritic cellsen
dc.subjectmacrophagesen
dc.subjectHELICOBACTER-PYLORIen
dc.subjectSENSITIVITY-ANALYSISen
dc.subjectHEALTHen
dc.subject.meshGastrointestinal Tracten
dc.subject.meshEpithelial Cellsen
dc.subject.meshImmune Systemen
dc.subject.meshAnimalsen
dc.subject.meshMiceen
dc.subject.meshHelicobacter pylorien
dc.subject.meshHelicobacter Infectionsen
dc.subject.meshCell Proliferationen
dc.subject.meshModels, Biologicalen
dc.subject.meshComputer Simulationen
dc.titleHigh-resolution computational modeling of immune responses in the guten
dc.title.serialGigaScienceen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2019-05-05en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Engineeringen
pubs.organisational-group/Virginia Tech/Engineering/Industrial and Systems Engineeringen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Biocomplexity Instituteen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Engineering/COE T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutes/Biocomplexity Institute/Researchersen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Durelle Scotten

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