{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:04:37Z","timestamp":1792649077187,"version":"4.5.0"},"reference-count":68,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2011,10,25]],"date-time":"2011-10-25T00:00:00Z","timestamp":1319500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2011,12,30]],"date-time":"2011-12-30T00:00:00Z","timestamp":1325203200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2011,12,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    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 \u201cuniversal placebo\u201d in microbicide trials. Cervicovaginal epithelial cultures were colonized with normal vaginal microflora isolates representing common\n                    <jats:italic>Lactobacillus<\/jats:italic>\n                    species used as probiotics (\n                    <jats:named-content content-type=\"genus-species\">L. acidophilus<\/jats:named-content>\n                    and\n                    <jats:named-content content-type=\"genus-species\">L. crispatus<\/jats:named-content>\n                    ) or\n                    <jats:named-content content-type=\"genus-species\">Prevotella bivia<\/jats:named-content>\n                    and\n                    <jats:named-content content-type=\"genus-species\">Atopobium vaginae<\/jats:named-content>\n                    , 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\n                    <jats:named-content content-type=\"genus-species\">L. crispatus<\/jats:named-content>\n                    . 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\n                    <jats:named-content content-type=\"genus-species\">L. acidophilus<\/jats:named-content>\n                    activated NF-\u03baB, although IL-8 and RANTES levels were increased by the presence of BV-causing bacteria only. CS enhanced NF-\u03baB activation in a dose-dependent manner under all conditions, including\n                    <jats:named-content content-type=\"genus-species\">L. acidophilus<\/jats:named-content>\n                    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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    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.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00168-11","type":"journal-article","created":{"date-parts":[[2011,10,25]],"date-time":"2011-10-25T23:00:55Z","timestamp":1319583655000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":77,"title":["Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action"],"prefix":"10.1128","volume":"2","author":[{"given":"Raina N.","family":"Fichorova","sequence":"first","affiliation":[{"name":"Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidemi S.","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary L.","family":"Delaney","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Onderdonk","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo F.","family":"Doncel","sequence":"additional","affiliation":[{"name":"CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod60.2.508"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.5.2424"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.9.5840-5848.2001"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00631-06"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2005.00287.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2004.00248.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/00126334-200410013-00008"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2010.09.018"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/00126334-200410013-00010"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1097\/00126334-200405010-00001"},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/j.1939-4640.2002.tb02250.x","article-title":"Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent","volume":"23","author":"Anderson RA","year":"2002","unstructured":"AndersonRA . 2002. 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