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, Marla J. Keller, Betsy Herold

Research output: Contribution to journalArticle

57 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Herpes Genitalis
Local Anti-Infective Agents
Nonoxynol
Anti-Infective Agents
Biomarkers
Inflammation
Safety
Placebos
Mucosal Immunity
Human Herpesvirus 2
Neutrophil Infiltration
Transcription Factor AP-1
Chemokines
Monocytes
Transcription Factors
Gels
Cytokines
PRO 2000

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

A comprehensive murine model to evaluate topical vaginal microbicides : Mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety. / Galen, Benjamin T.; Martin, Andrea P.; Hazrati, Ehsan; Garin, Alexandre; Guzman, Esmeralda; Wilson, Sarah S.; Porter, David D.; Lira, Sergio A.; Keller, Marla J.; Herold, Betsy.

In: Journal of Infectious Diseases, Vol. 195, No. 9, 01.05.2007, p. 1332-1339.

Research output: Contribution to journalArticle

Galen, Benjamin T. ; Martin, Andrea P. ; Hazrati, Ehsan ; Garin, Alexandre ; Guzman, Esmeralda ; Wilson, Sarah S. ; Porter, David D. ; Lira, Sergio A. ; Keller, Marla J. ; Herold, Betsy. / A comprehensive murine model to evaluate topical vaginal microbicides : Mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety. In: Journal of Infectious Diseases. 2007 ; Vol. 195, No. 9. pp. 1332-1339.
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