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

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...

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Autores principales:	Raina N. Fichorova, Hidemi S. Yamamoto, Mary L. Delaney, Andrew B. Onderdonk, Gustavo F. Doncel
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2011
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c02cf8723ae24c2f9533b469c83e2261
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spelling	oai:doaj.org-article:c02cf8723ae24c2f9533b469c83e22612021-11-15T15:38:48ZNovel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action10.1128/mBio.00168-112150-7511https://doaj.org/article/c02cf8723ae24c2f9533b469c83e22612011-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00168-11https://doaj.org/toc/2150-7511ABSTRACT 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.Raina N. FichorovaHidemi S. YamamotoMary L. DelaneyAndrew B. OnderdonkGustavo F. DoncelAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 2, Iss 6 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Raina N. Fichorova Hidemi S. Yamamoto Mary L. Delaney Andrew B. Onderdonk Gustavo F. Doncel Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action
description	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.
format	article
author	Raina N. Fichorova Hidemi S. Yamamoto Mary L. Delaney Andrew B. Onderdonk Gustavo F. Doncel
author_facet	Raina N. Fichorova Hidemi S. Yamamoto Mary L. Delaney Andrew B. Onderdonk Gustavo F. Doncel
author_sort	Raina N. Fichorova
title	Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action
title_short	Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action
title_full	Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action
title_fullStr	Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action
title_full_unstemmed	Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action
title_sort	novel vaginal microflora colonization model providing new insight into microbicide mechanism of action
publisher	American Society for Microbiology
publishDate	2011
url	https://doaj.org/article/c02cf8723ae24c2f9533b469c83e2261
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Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action

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