A comprehensive murine model to evaluate topical vaginal microbicides: Mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety

Benjamin T. Galen, Andrea P. Martin, Ehsan Hazrati, Alexandre Garin, Esmeralda Guzman, Sarah S. Wilson, David D. Porter, Sergio A. Lira, Maria J. Keller, Betsy C. Herold

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

A critical gap in microbicide development is the absence of surrogate safety markers. The objective of the present study was to develop a murine model to examine the mucosal response to microbicides and to assess the functional implication of observed changes. Mice received 14 daily intravaginal doses of nonoxynol-9, PRO 2000, or placebo gel. Nonoxynol-9 induced an inflammatory response characterized by increases in levels of cytokines and chemokines, recruitment of neutrophils and monocytes into the genital tract, and activation of the transcription factors NF-κB and activator protein-1. Minimal inflammation was observed in response to 2% PRO 2000. Nonoxynol-9-treated mice were significantly more susceptible to challenge with a low dose of herpes simplex virus type 2; the response of PRO 2000-treated mice was similar to the response to placebo. These findings suggest that PRO 2000 has little deleterious effect on mucosal immunity and, if validated by clinical experiences, support the inclusion of this model in the preclinical evaluation of future candidate microbicides.

Original languageEnglish (US)
Pages (from-to)1332-1339
Number of pages8
JournalJournal of Infectious Diseases
Volume195
Issue number9
DOIs
StatePublished - May 1 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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