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

DSpace/Manakin Repository

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

Show simple item record


dc.contributor.advisor Richard B. Pyles en_US
dc.creator William Alfred Rose II en_US
dc.date.accessioned 2011-12-20T16:05:26Z
dc.date.available 2010-09-28 en_US
dc.date.available 2011-12-20T16:05:26Z
dc.date.created 2009-10-29 en_US
dc.date.issued 2009-10-16 en_US
dc.identifier.other etd-10292009-142513 en_US
dc.identifier.uri http://hdl.handle.net/2152.3/243
dc.description.abstract Herpes 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.medium electronic en_US
dc.language.iso eng en_US
dc.rights Copyright © 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.subject vaginal model en_US
dc.subject TLR en_US
dc.subject immunomodulatory compound en_US
dc.subject herpes simplex virus en_US
dc.subject genital epithelia en_US
dc.subject commensal bacteria en_US
dc.title Evaluation of immunomodulatory compounds for identification of an anti-herpetic innate immune response profile en_US
dc.type.material text en_US
dc.type.genre dissertation en_US
thesis.degree.name PhD en_US
thesis.degree.level Doctoral en_US
thesis.degree.grantor The University of Texas Medical Branch en_US
thesis.degree.department Microbiology and Immunology en_US
dc.contributor.committeeMember Tonyia D. Eaves-Pyles en_US
dc.contributor.committeeMember Joan E. Nichols en_US
dc.contributor.committeeMember James W. LeDuc en_US
dc.contributor.committeeMember Alison J. Quayle en_US

Files in this item

Files Size Format View
William_A_Rose_II_Dissertation.pdf 2.721Mb PDF View/Open

This item appears in the following Collection(s)

Show simple item record

Search DSpace


Advanced Search

Browse

My Account