Laboratory of Innate Host Defense, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
Student Health Services, University of Central Florida, Orlando, Florida, USA.
Infect Immun. 2020 Mar 23;88(4). doi: 10.1128/IAI.00041-20.
Bacterial vaginosis (BV), a disorder of the female reproductive tract (FRT) in which a healthy -dominant microflora is replaced by BV-associated bacteria (BVAB), can significantly increase the incidence of human immunodeficiency virus (HIV) acquisition. Discerning the effect of BV on the mucosal epithelium of the FRT may yield novel preventatives and therapeutics for HIV infection. Here, we investigated barrier dysfunction of the endocervix by host-derived factors, secreted in response to BV, as a potential cause of HIV infection. Using a polarized endocervical cell culture system, we determined that conditioned media (CM) from endocervical cells cocultured with BVAB (endocervical+BVAB CM), as well as cervicovaginal fluid (CVF) from women with BV, disrupted epithelial polarization. We assessed host matrix metalloproteinases (MMPs) as the BV-associated secreted factors which disrupt the endocervical epithelium. MMPs were overexpressed in endocervical+BVAB CM and CVF from women with BV and were capable of disrupting endocervical epithelial polarization. When we cocultured polarized endocervical cells with HIV-1-infected lymphocyte-derived cells, we discovered endocervical+BVAB CM and MMPs significantly increased the transmigration of virus through the epithelium, and treatment with an MMP inhibitor decreased these effects. When we examined the effect of CVF on HIV-1 transmigration through endocervical epithelium, we demonstrated that CVF samples with greater concentrations of BV-associated MMPs increased viral transmigration. Our results suggest MMPs increase HIV-1 infection by disrupting the endocervical epithelium, permitting transmigration of virus through the epithelium to infect underlying target cells.
细菌性阴道病（BV）是一种女性生殖道（FRT）疾病，其中健康主导的微生物群被 BV 相关细菌（BVAB）取代，可显著增加人类免疫缺陷病毒（HIV）的感染率。了解 BV 对 FRT 黏膜上皮的影响可能为 HIV 感染提供新的预防和治疗方法。在这里，我们研究了由宿主来源的因素引起的内颈管屏障功能障碍，这些因素是对 BV 的反应而分泌的，这可能是 HIV 感染的潜在原因。使用极化的内颈管细胞培养系统，我们确定了与 BVAB 共培养的内颈管细胞的条件培养基（CM）（内颈管+BVAB CM）以及患有 BV 的女性的宫颈阴道分泌物（CVF）破坏了上皮细胞的极化。我们评估了宿主基质金属蛋白酶（MMPs）作为破坏内颈管上皮的与 BV 相关的分泌因子。内颈管+BVAB CM 和患有 BV 的女性的 CVF 中 MMPs 过度表达，并且能够破坏内颈管上皮的极化。当我们将极化的内颈管细胞与 HIV-1 感染的淋巴细胞衍生细胞共培养时，我们发现内颈管+BVAB CM 和 MMPs 显著增加了病毒通过上皮细胞的迁移，并且 MMP 抑制剂的治疗降低了这些作用。当我们检查 CVF 对 HIV-1 通过内颈管上皮迁移的影响时，我们证明具有更高浓度与 BV 相关的 MMP 的 CVF 样本增加了病毒的迁移。我们的研究结果表明，MMP 通过破坏内颈管上皮增加了 HIV-1 的感染，从而允许病毒通过上皮细胞迁移以感染下面的靶细胞。
