A co-infection model for papillomavirus associated infections and cancers

摘要 HPV感染是最常见的性传播疾病，也是宫颈癌的主要原因。 宫颈癌仍然是第四大最常见的女性恶性肿瘤和第二大最常见的女性恶性肿瘤。 女性癌症发生在15至44岁的女性中，估计造成91%的HPV相关癌症死亡。 美国每年约有550万例新的HPV感染;尽管90%的感染 可以在两年内清除，约10%的持续性HPV感染最终会进展为侵袭性 癌的目前的预防性HPV疫苗（Gardasil和Cervarix）不能清除已建立的感染， 可能需要25年才能发展成恶性肿瘤HPV相关癌症的临床管理是 具有挑战性，因为强大的早期诊断和治愈性治疗尚未开发。HPV 持续性是宫颈癌的一个关键因素。越来越多的证据表明， 高水平的细菌性阴道病（BV）相关厌氧菌感染HPV的风险增加 持久性。然而，BV在宫颈癌中的原因/影响仍然难以捉摸。令人惊讶的是， 关于BV相关细菌和HPV之间关系的分子过程 因为共感染模型系统尚未建立。吉尔伯特博士的跨学科团队， 阴道微生物组和胡博士对于乳头瘤病毒将最适合建立一个共感染模型来研究 阴道细菌和乳头瘤病毒在宫颈癌发展中的动态作用。我们 指导这一建议的主要假设是BV细菌促进HPV持久性和肿瘤 进展，性激素避孕药通过破坏阴道分泌物促进HPV持续存在和癌症。 微生物组更具体地说，我们将在当前提案的两个具体目标中测试这些假设：1）BV 细菌通过降解阴道粘液屏障，扰乱阴道粘膜， 上皮和/或调节宿主对HPV感染的炎症反应（目的1）。2)性激素 避孕药通过破坏阴道微生物组促进HPV持续存在和生殖道癌症 (Aim 2）。这些目标的理由是基于以前发表的研究和当前的需求。两 常见的避孕药醋酸甲羟孕酮（DMPA）和17 β-雌二醇可能会损害 乳酸杆菌定植，并可能损害阴道屏障，导致HPV病毒感染 坚持和癌症我们将根据以下专家的专业知识开发新的合并感染小鼠模型系统： 两个团队在两个新的小鼠模型，有必要直接检查我们的假设， 两个具体目标。这些研究将为更详细的微生物和生物化学研究提供起点。 检查宫颈癌中BV-HPV相关性的驱动机制。目前的调查结果 拟议的研究将有重大意义，不仅在提供新的见解，阴道 微生物组和乳头瘤病毒领域，而且还在确定未来转化研究的干预措施。

Abstract HPV infections are the most common sexually transmitted diseases and the primary cause of cervical cancer. Cervical cancer remains to be the fourth most common female malignancy and the second most common female cancer in women aged 15 to 44 years and is estimated to cause 91% of HPV-related cancer deaths. Every year approximately 5.5 million new HPV infections are reported in the U.S; Although 90% of infections can be cleared within two years, about 10% persistent HPV infections will ultimately progress to invasive cancers. The current prophylactic HPV vaccines (Gardasil and Cervarix) cannot clear established infections, which could take up to 25 years to progress to malignancy. Clinical management of HPV-related cancers is challenging because the robust early diagnostics and curative treatments are yet to be developed. HPV persistence is one key factor for cervical cancer. Accumulated evidence has demonstrated that women with high levels of bacterial vaginosis (BV)-associated anaerobic organisms are at increased risk of HPV persistence. However, the cause/effect of BV in cervical cancer remains elusive. Surprisingly little is known about the molecular processes underpinning the relationship between BV-associated bacteria and HPV because co-infection model systems have not been established. The interdisciplinary team of Dr. Gilbert for vaginal microbiome and Dr. Hu for papillomavirus will be most suitable to develop a co-infection model to study the dynamic roles of vaginal bacteria and papillomavirus persistence during cervical cancer development. Our overarching hypotheses guiding this proposal are that BV bacteria promote HPV persistence and tumor progression, and sex hormone contraceptives promote HPV persistence and cancer by disrupting the vaginal microbiome. More specifically, we will test these hypotheses in two specific aims of the current proposal: 1) BV bacteria promote HPV persistence and cancers by degrading the vaginal mucus barrier, disturbing the vaginal epithelium and/or by modulating host inflammatory responses to HPV infections (Aim 1). 2) Sex hormonal contraceptives promote HPV persistence and cancer in the genital tract by disrupting the vaginal microbiome (Aim 2). The rationales for these aims are based on previous published studies and current needs. Two common contraceptives depo medroxy-progesterone acetate (DMPA) and 17 beta-estradiol may impair colonization of lactobacilli and possibly compromise the vaginal barrier to viral infections leading to HPV persistence and cancer. We will develop a new co-infection mouse model system based on the expertise of two teams in two novel mouse models necessary to directly examine the basic premise of our hypotheses in two specific Aims. These studies will provide a starting place for more detailed microbiological and biochemical examinations of the mechanisms driving the BV-HPV association in cervical cancer. Findings of the current proposed study will have significant implications not only in providing novel insight to both the vaginal microbiome and papillomavirus fields but also in identifying interventions for future translational studies.