Matrix Metalloproteinases Expressed in Response to Bacterial Vaginosis Disrupt the Endocervical Epithelium, Increasing Transmigration of HIV
Matrix Metalloproteinases Expressed in Response to Bacterial Vaginosis Disrupt the Endocervical Epithelium, Increasing Transmigration of HIV
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DOI：
10.1128/iai.00041-20
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发表时间：
2020-04-01
影响因子：
3.1
通讯作者：
Cole, Alexander M.
中科院分区：
文献类型：
--
作者：
Cherne, Michelle D.;Cole, Amy L.;Cole, Alexander M.
细菌性阴道病（BV）是一种女性生殖道（FRT）疾病，其中健康的乳杆菌属优势菌群被BV相关细菌（BVAB）取代，可显著增加人类免疫缺陷病毒（HIV）感染的发生率。辨别BV对FRT粘膜上皮的影响可能会产生新的预防和治疗HIV感染的药物。在这里，我们研究了宿主源性因子引起的宫颈内膜屏障功能障碍，这些因子是对BV的反应而分泌的，是HIV感染的潜在原因。使用极化宫颈内细胞培养系统，我们确定，条件培养基（CM）的宫颈内细胞共培养BVAB（宫颈+BVAB CM），以及宫颈阴道液（CVF）的妇女与BV，破坏上皮极化。我们评估宿主基质金属蛋白酶（MMPs）作为BV相关的分泌因子，破坏宫颈上皮。基质金属蛋白酶在BV妇女宫颈内+BVAB CM和CVF中过表达，能够破坏宫颈内上皮极化。当我们将极化的宫颈内细胞与HIV-1感染的淋巴细胞衍生的细胞共培养时，我们发现宫颈内+BVAB CM和MMP显著增加了病毒通过上皮的迁移，并且用MMP抑制剂治疗降低了这些影响。当我们检查CVF对HIV-1通过宫颈上皮细胞迁移的影响时，我们证明了具有更高浓度BV相关MMPs的CVF样品增加了病毒的迁移。我们的研究结果表明，基质金属蛋白酶增加HIV-1感染的破坏宫颈上皮，允许通过上皮细胞感染下面的靶细胞的病毒transmigration。
Bacterial vaginosis (BV), a disorder of the female reproductive tract (FRT) in which a healthy Lactobacillus-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.