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Endothelial Cell Proteomic Response to Rickettsia conorii Infection Reveals Activation of the Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT)-Inferferon Stimulated Gene (ISG)15 Pathway and Reprogramming Plasma Membrane Integrin/Cadherin Signaling

2016-01Journal article Open access
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dc.contributor.authorZhao, Yingxin
dc.contributor.authorValbuena, Gustavo
dc.contributor.authorWalker, David H.
dc.contributor.authorGazi, Michal
dc.contributor.authorHidalgo, Marylin
dc.contributor.authorDe Sousa, Rita
dc.contributor.authorOteo, Jose Antonio
dc.contributor.authorGoez, Yenny
dc.contributor.authorBrasier, Allan R.
dc.date.accessioned2017-03-07T15:46:25Z
dc.date.available2017-03-07T15:46:25Z
dc.date.issued2016-01
dc.descriptionFree PMC Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762516/pt_PT
dc.description.abstractRickettsia conorii is the etiologic agent of Mediterranean spotted fever, a re-emerging infectious disease with significant mortality. This Gram-negative, obligately intracellular pathogen is transmitted via tick bites, resulting in disseminated vascular endothelial cell infection with vascular leakage. In the infected human, Rickettsia conorii infects endothelial cells, stimulating expression of cytokines and pro-coagulant factors. However, the integrated proteomic response of human endothelial cells to R. conorii infection is not known. In this study, we performed quantitative proteomic profiling of primary human umbilical vein endothelial cells (HUVECs) with established R conorii infection versus those stimulated with endotoxin (LPS) alone. We observed differential expression of 55 proteins in HUVEC whole cell lysates. Of these, we observed induction of signal transducer and activator of transcription (STAT)1, MX dynamin-like GTPase (MX1), and ISG15 ubiquitin-like modifier, indicating activation of the JAK-STAT signaling pathway occurs in R. conorii-infected HUVECs. The down-regulated proteins included those involved in the pyrimidine and arginine biosynthetic pathways. A highly specific biotinylated cross-linking enrichment protocol was performed to identify dysregulation of 11 integral plasma membrane proteins that included up-regulated expression of a sodium/potassium transporter and down-regulation of α-actin 1. Analysis of Golgi and soluble Golgi fractions identified up-regulated proteins involved in platelet-endothelial adhesion, phospholipase activity, and IFN activity. Thirty four rickettsial proteins were identified with high confidence in the Golgi, plasma membrane, or secreted protein fractions. The host proteins associated with rickettsial infections indicate activation of interferon-STAT signaling pathways; the disruption of cellular adhesion and alteration of antigen presentation pathways in response to rickettsial infections are distinct from those produced by nonspecific LPS stimulation. These patterns of differentially expressed proteins suggest mechanisms of pathogenesis as well as methods for diagnosis and monitoring Rickettsia infections.pt_PT
dc.description.sponsorshipThis work was supported by NIAID Clinical Proteomics Center Grant HHSN272200800048C (to A.R.B.), University of Texas Medical Branch Clinical and Translational Science Award (CTSA) UL1TR000071 (to A.R.B.), and NIEHS Grant P30 ES006676 (to A.R.B.).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMol Cell Proteomics. 2016 Jan;15(1):289-304. doi: 10.1074/mcp.M115.054361. Epub 2015 Nov 11pt_PT
dc.identifier.doi10.1074/mcp.M115.054361pt_PT
dc.identifier.issn1535-9476
dc.identifier.urihttp://hdl.handle.net/10400.18/4547
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Society for Biochemistry and Molecular Biologypt_PT
dc.relation.publisherversionhttp://www.mcponline.org/content/15/1/289.longpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectCadherinspt_PT
dc.subjectCell Membranept_PT
dc.subjectCells, Culturedpt_PT
dc.subjectChromatography, Liquidpt_PT
dc.subjectCytokinespt_PT
dc.subjectGolgi Apparatuspt_PT
dc.subjectHost-Pathogen Interactionspt_PT
dc.subjectHuman Umbilical Vein Endothelial Cellspt_PT
dc.subjectHumanspt_PT
dc.subjectIntegrinspt_PT
dc.subjectJanus Kinasespt_PT
dc.subjectLipopolysaccharidespt_PT
dc.subjectMembrane Proteinspt_PT
dc.subjectProteomept_PT
dc.subjectProteomicspt_PT
dc.subjectRickettsia conoriipt_PT
dc.subjectSTAT1 Transcription Factorpt_PT
dc.subjectSignal Transductionpt_PT
dc.subjectTandem Mass Spectrometrypt_PT
dc.subjectUbiquitinspt_PT
dc.subjectInfecções Sistémicas e Zoonosespt_PT
dc.titleEndothelial Cell Proteomic Response to Rickettsia conorii Infection Reveals Activation of the Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT)-Inferferon Stimulated Gene (ISG)15 Pathway and Reprogramming Plasma Membrane Integrin/Cadherin Signalingpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage304pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage289pt_PT
oaire.citation.titleMolecular and Cellular Proteomicspt_PT
oaire.citation.volume15pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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