Evaluation of immunomodulatory compounds for identification of an anti-herpetic innate immune response profile

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dc.contributor.advisorRichard B. Pylesen_US
dc.contributor.committeeMemberTonyia D. Eaves-Pylesen_US
dc.contributor.committeeMemberJoan E. Nicholsen_US
dc.contributor.committeeMemberJames W. LeDucen_US
dc.contributor.committeeMemberAlison J. Quayleen_US
dc.creatorWilliam Alfred Rose IIen_US
dc.date.accessioned2011-12-20T16:05:26Z
dc.date.available2010-09-28en_US
dc.date.available2011-12-20T16:05:26Z
dc.date.created2009-10-29en_US
dc.date.issued2009-10-16en_US
dc.description.abstractHerpes simplex virus type 2 (HSV-2) is a prevalent world-wide sexually transmitted infection (STI) that commonly infects the genital mucosa and establishes a life-long latent infection. The virus periodically reactivates producing recurrent shedding episodes that increase the risk of acquiring other STI. There are no FDA-approved HSV-2 vaccines and treatment involves chronic therapy that does not prevent all recurrences; therefore novel anti-herpetic intervention strategies are needed that provide resistance to HSV-2 infection. Because genital HSV-2 infections are more prevalent in women than men, most anti-herpetic strategies focus on vaginal application. One promising intervention involves the use of immunomodulatory compounds to engender an HSV-2 resistant environment by stimulating the natural innate immune defenses of the vaginal mucosa. The compounds consist of evolutionarily conserved pathogen-associated molecular patterns termed toll-like receptor (TLR) agonists that are recognized by vaginally expressed TLR and elicit specific cytokine response profiles. As an initial step in identifying cytokines that are associated with resistance to HSV-2 infection, selected TLR agonists were evaluated in human cell culture or small animal models. An assay scheme was developed to identify anti-herpetic and non-anti-herpetic compounds and identified, for the first time, fibroblast stimulating ligand-1 as a novel anti-herpetic TLR agonist. Immunological evaluations of the compounds in human vaginal epithelial cells (EC) identified IL-2, IL-12(p70), IFN, MIP-1, MIP-1 and RANTES as important for establishing an HSV-2 resistant environment. The profile was confirmed and expanded to include IL-12(p40) and IFN following evaluations in a mouse model of genital HSV-2 infection. Additionally, the profile was observed in a novel in vitro air-interface vaginal EC model of the human vaginal mucosa. Colonization of the in vitro model with common vaginal commensal bacteria showed a temporally-dependent tempering of the TLR agonist elicited cytokine response and enhancement of agonist induced anti-herpetic activity. The identified anti-herpetic cytokine response profile provides an invaluable resource for the future design of novel immunomodulatory compounds that will aid in reducing HSV-2 transmission world-wide. Additionally, the studies in the novel in vitro model of the human vaginal mucosa showed that commensal bacterial play an important role in the vaginal defenses against pathogenic infection.en_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-10292009-142513en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/243
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.subjectvaginal modelen_US
dc.subjectTLRen_US
dc.subjectimmunomodulatory compounden_US
dc.subjectherpes simplex virusen_US
dc.subjectgenital epitheliaen_US
dc.subjectcommensal bacteriaen_US
dc.titleEvaluation of immunomodulatory compounds for identification of an anti-herpetic innate immune response profileen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentMicrobiology and Immunologyen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

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