Cytokine patterns in a comparative model of arenavirus infection: Implications for virulence and control of viral replication

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dc.contributor.advisorJudith Aronsonen_US
dc.contributor.committeeMemberThomas K. Hughesen_US
dc.contributor.committeeMemberLynn Soongen_US
dc.contributor.committeeMemberDavid N. McMurrayen_US
dc.contributor.committeeMemberClarence J. Petersen_US
dc.creatorErin P. Scotten_US
dc.date.accessioned2011-12-20T16:04:57Z
dc.date.available2008-06-17en_US
dc.date.available2011-12-20T16:04:57Z
dc.date.created2005-07-18en_US
dc.date.issued2005-07-12en_US
dc.description.abstractGuinea pig infection with the arenavirus Pichinde provides an animal model for human Lassa fever, a disease that affects 300,000 to 500,000 people a year in western Africa. Low passage Pichinde virus (P2) induces a mild disease with low viremia, while high passage Pichinde (P18) induces a severe disease with high viremia, ending in terminal shock. We hypothesized that severe disease would be associated with a suppression of potentially antiviral cytokines early in infection, and high levels of potentially pathogenic pro-inflammatory cytokines late in infection. Cytokine responses to P2 and P18 infection were measured from primary guinea pig peritoneal macrophages (PM) in vitro when measured by real time RT-PCR. In general, neither P2 nor P18 infection altered cytokine production from unstimulated PM. P18 infected PM did have lower mRNA levels of IL-1beta, IL-12p40, and MCP-1 after LPS addition when compared to P2 infected PM. During experimental guinea pig infection, P18 infection was associated with markedly increased IFN-gamma and MCP-1 mRNA levels from the initial peritoneal target cells relative to P2. P18 infected peritoneal cells had slightly decreased TNF-alpha, IL-8, and IL-12p40 transcripts relative to mock infected peritoneal cells. Late in infection, P18 infected spleens and livers had similar cytokine patterns relative to P2, but P18 infected PBL had decreased TNF-alpha, IFN-gamma, and RANTES transcripts. We also examined the ability of a decoy AP-1 thioaptamer, XBY-S2, to alter morbidity, mortality, and cytokine expression during P18 infection of guinea pigs. After two doses of XBY-S2, 50% (p=.024) of treated guinea pigs survived infection and had undetectable viremia. XBY-S2-treated P18 infected guinea pigs over time had overall increased cytokine mRNA expression of TNF-alpha, IL-8, IL-1beta, and IL-10 compared to PBS-treated P18 infected guinea pigs. A suppression of PBL IL-1beta and RANTES mRNA at day 12 of P18 infection was repeatedly observed. Conclusions from these experiments are 1) macrophage-derived cytokines do not explain the differential replication of P2 and P18 viruses, 2) high levels of IFN-gamma and MCP-1 may contribute to virulence of P18 virus, 3) over-expression of pro-inflammatory cytokines in PBL, liver, or spleen is not associated with terminal shock, 4) boosting of pro-inflammatory cytokines by an AP-1 aptamer correlates with reduced viremia and survival of P18 infection.en_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-07182005-142738en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/163
dc.language.isoengen_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.subjectviral hemorrhagic feveren_US
dc.subjectinnate immunityen_US
dc.titleCytokine patterns in a comparative model of arenavirus infection: Implications for virulence and control of viral replicationen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentExperimental Pathologyen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

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