PDF(Pubmed)
Abstract：
Human papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States and are a major etiological agent of cancers in the anogenital tract and oral cavity. Growing evidence suggests changes in the host microbiome are associated with the natural history and ultimate outcome of HPV infection. We sought to define changes in the host cervicovaginal microbiome during papillomavirus infection, persistence, and pathogenesis using the murine papillomavirus (MmuPV1) cervicovaginal infection model. Cervicovaginal lavages were performed over a time course of MmuPV1 infection in immunocompetent female FVB/N mice and extracted DNA was analyzed by qPCR to track MmuPV1 viral copy number. 16S ribosomal RNA (rRNA) gene sequencing was used to determine the composition and diversity of microbial communities throughout this time course. We also sought to determine whether specific microbial communities exist across the spectrum of MmuPV1-induced neoplastic disease. We, therefore, performed laser-capture microdissection to isolate regions of disease representing all stages of neoplastic disease progression (normal, low- and high-grade dysplasia, and cancer) from female reproductive tract tissue sections from MmuPV1-infected mice and performed 16S rRNA sequencing. Consistent with other studies, we found that the natural murine cervicovaginal microbiome is highly variable across different experiments. Despite these differences in initial microbiome composition between experiments, we observed that MmuPV1 persistence, viral load, and severity of disease influenced the composition of the cervicovaginal microbiome. These studies demonstrate that papillomavirus infection can alter the cervicovaginal microbiome.IMPORTANCEHuman papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States. A subset of HPVs that infect the anogenital tract (cervix, vagina, anus) and oral cavity cause at least 5% of cancers worldwide. Recent evidence indicates that the community of microbial organisms present in the human cervix and vagina, known as the cervicovaginal microbiome, plays a role in HPV-induced cervical cancer. However, the mechanisms underlying this interplay are not well-defined. In this study, we infected the female reproductive tract of mice with a murine papillomavirus (MmuPV1) and found that key aspects of papillomavirus infection and disease influence the host cervicovaginal microbiome. This is the first study to define changes in the host microbiome associated with MmuPV1 infection in a preclinical animal model of HPV-induced cervical cancer. These results pave the way for using MmuPV1 infection models to further investigate the interactions between papillomaviruses and the host microbiome.
摘要：
人乳头瘤病毒（HPV）是美国最常见的性传播感染，是肛门生殖道和口腔癌的主要病因。越来越多的证据表明，宿主微生物组的变化与HPV感染的自然史和最终结果有关。我们试图定义乳头瘤病毒感染期间宿主宫颈阴道微生物组的变化，持久性,和发病机制使用小鼠乳头瘤病毒（MmuPV1）宫颈阴道感染模型。在具有免疫能力的雌性FVB/N小鼠中MmuPV1感染的时间过程中进行宫颈阴道灌洗，并通过qPCR分析提取的DNA以跟踪MmuPV1病毒拷贝数。16S核糖体RNA（rRNA）基因测序用于确定整个时间过程中微生物群落的组成和多样性。我们还试图确定特定的微生物群落是否存在于MmuPV1诱导的肿瘤性疾病的范围内。我们,因此,进行激光捕获显微切割，以分离代表肿瘤疾病进展所有阶段的疾病区域(正常，低级和高级发育不良，和癌症）来自MmuPV1感染小鼠的雌性生殖道组织切片，并进行了16SrRNA测序。与其他研究一致，我们发现，天然小鼠宫颈阴道微生物组在不同的实验中是高度可变的。尽管实验之间的初始微生物组组成存在差异，我们观察到MmuPV1持久性，病毒载量,和疾病的严重程度影响宫颈阴道微生物组的组成。这些研究表明，乳头瘤病毒感染可以改变宫颈阴道微生物组。重要的人乳头瘤病毒（HPVs）是美国最常见的性传播感染。感染肛门生殖道的HPV子集（子宫颈，阴道,肛门）和口腔导致全球至少5%的癌症。最近的证据表明，存在于人类子宫颈和阴道中的微生物群落，被称为宫颈阴道微生物组，在HPV诱导的宫颈癌中起作用。然而,这种相互作用背后的机制并不明确。在这项研究中,我们用小鼠乳头瘤病毒（MmuPV1）感染小鼠的雌性生殖道，发现乳头瘤病毒感染和疾病的关键方面影响宿主宫颈阴道微生物组。这是第一项在HPV诱导的宫颈癌的临床前动物模型中定义与MmuPV1感染相关的宿主微生物组变化的研究。这些结果为使用MmuPV1感染模型进一步研究乳头状瘤病毒与宿主微生物组之间的相互作用铺平了道路。
