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Research Article

Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action

Raina N. Fichorova, Hidemi S. Yamamoto, Mary L. Delaney, Andrew B. Onderdonk, Gustavo F. Doncel
Peter Gilligan, Editor
Raina N. Fichorova
Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Hidemi S. Yamamoto
Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Mary L. Delaney
Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Andrew B. Onderdonk
Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Gustavo F. Doncel
CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia, USA
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Peter Gilligan
UNC Health Care System
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DOI: 10.1128/mBio.00168-11
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ABSTRACT

Several broad-spectrum microbicides, including cellulose sulfate (CS), have passed conventional preclinical and phase I clinical safety evaluation and yet have failed to protect women from acquiring HIV-1 in phase II/III trials. Concerns have been raised that current preclinical algorithms are deficient in addressing the complexity of the microflora-regulated vaginal mucosal barrier. We applied a novel microflora-colonized model to evaluate CS and hydroxyethylcellulose (HEC), which is used as a “universal placebo” in microbicide trials. Cervicovaginal epithelial cultures were colonized with normal vaginal microflora isolates representing common Lactobacillus species used as probiotics (L. acidophilus and L. crispatus) or Prevotella bivia and Atopobium vaginae, most prevalent in the disturbed microflora of bacterial vaginosis (BV). At baseline, all strains maintained constant epithelium-associated CFUs without inducing cytotoxicity and apoptosis. CS selectively reduced epithelium-associated CFUs and (to a lesser extent) planktonic CFUs, most significantly affecting L. crispatus. Inducing only minor changes in sterile epithelial cultures, CS induced expression of innate immunity mediators (RANTES, interleukin-8 [IL-8], and secretory leukocyte protease inhibitor [SLPI]) in microflora-colonized epithelia, most significantly potentiating effects of bacteria causing BV. In the absence of CS, all bacterial strains except L. acidophilus activated NF-κB, although IL-8 and RANTES levels were increased by the presence of BV-causing bacteria only. CS enhanced NF-κB activation in a dose-dependent manner under all conditions, including L. acidophilus colonization. HEC remained inert. These results offer insights into possible mechanisms of CS clinical failure. The bacterially colonized cervicovaginal model reveals unique aspects of microflora-epithelium-drug interactions and innate immunity in the female genital tract and should become an integral part of preclinical safety evaluation of anti-HIV microbicides and other vaginal formulations.

IMPORTANCE This report provides experimental evidence supporting the concept that the vaginal microflora regulates the epithelial innate immunity in a species- and strain-specific manner and that topically applied microbicides may alter both the bacterial and epithelial components of this homeostatic interaction. Our data also highlight the importance of differentiating the effects of biomedical interventions on epithelium-associated versus conventional planktonic bacterial growth when assessing vaginal mucosal health and immunity.

  • Copyright © 2011 Fichorova et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action
Raina N. Fichorova, Hidemi S. Yamamoto, Mary L. Delaney, Andrew B. Onderdonk, Gustavo F. Doncel
mBio Oct 2011, 2 (6) e00168-11; DOI: 10.1128/mBio.00168-11

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Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action
Raina N. Fichorova, Hidemi S. Yamamoto, Mary L. Delaney, Andrew B. Onderdonk, Gustavo F. Doncel
mBio Oct 2011, 2 (6) e00168-11; DOI: 10.1128/mBio.00168-11
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