The role of bacterial vaginosis-associated bacteria in papillomavirus persistence and cancers

摘要 HPV是世界上最常见的性传播疾病之一， 占人类癌症的5%。大多数宫颈癌（>96%）和口咽癌（70%）的病例是 与HPV感染有关。虽然目前的HPV疫苗已经成功地降低了 在接种人群中覆盖的HPV型别中，疫苗未覆盖的HPV型别的流行率仍然很高。 目前，数百万先前存在HPV感染的个体没有治愈性治疗。我们 拟议的研究旨在解决PAR-20-061中提出的知识差距，以了解“共同的作用”， 感染在癌症病因学和进展中的作用”。新兴的实验和观察研究 表明阴道微生物群可能在HPV相关疾病进展为癌症中起关键作用。 我们建议测试几个新的假设，包括阴道细菌及其代谢产物作为潜在的 与人类宫颈癌的进展/消退相关的免疫应答的驱动因子或抑制因子。 在健康女性中，阴道微生物环境由多种微生物， 微生物组谱（CST-I）。几种非微生物种属，包括多种微生物的微生物组谱 （CST-III和-IV）与HPV感染/持续性和瘤形成增加相关。 有趣的是，在阴道中具有相对较小的CST-I群落的个体通常 由非细菌性大肠杆菌（CST-III和CST-IV）定殖，这是BV的特征。我们初步的体内试验 研究表明，非细菌性阴道加德纳菌和穆氏动弯菌 （CST-IV）改变了炎症通路，从而提示G. vagelis和M. Mulieris可以促进 乳头瘤病毒在生殖道中的持续存在。我们假设乳头状瘤病毒与BV- 相关细菌促进病毒持续存在和生殖器粘膜发育不良。为了验证我们的假设，我们将 使用我们新的小鼠乳头瘤病毒和阴道细菌感染模型来1）确定 内源性阴道微生物群与免疫功能低下和免疫功能低下患者的高阴道发育不良相关， 和免疫活性小鼠（目的1）; 2）确定BV相关细菌和 代谢物和乳头瘤病毒相关的肿瘤进展（目的2）。这是第一个这样的研究， 微生物组和乳头瘤病毒领域。我们的发现将揭示一个研究不足但重要的问题， 宫颈癌的发展与人类有关。

ABSTRACT HPV is one of the most common sexually transmitted diseases worldwide and is the caustic factor for about 5% of all human cancers. Most cases of cervical cancer (>96%) and oropharyngeal cancer (70%) are associated with HPV infections. Although current HPV vaccines have successfully decreased the prevalence of HPV types covered in the vaccinated groups, the prevalence of HPV types not covered by vaccines is still high. Currently, no curative treatments are available to millions of individuals with preexisting HPV infections. Our proposed study aims to address the knowledge gap raised in PAR-20-061 in understanding “the role of co- infection in cancer etiology and progression”. Emerging experimental and observational studies have demonstrated that vaginal microbiota may play a critical role in HPV-associated disease progression to cancer. We propose to test several novel hypotheses including vaginal bacteria and their metabolites as potential drivers or suppressors of immune responses linked with progression/regression of cervical cancers in humans. In healthy women, the vaginal microbial environment is dominated by lactobacillus species, polymicrobial microbiome profiles (CST-I). Several non-lactobacillus species, including polymicrobial microbiome profiles (CST-III and -IV), are associated with increased HPV infection/persistence and neoplasia formation. Interestingly, individuals with a relatively small lactobacillus (CST-I) community in the vagina are commonly colonized by non-lactobacillus bacteria (CST-III and -IV), which is characteristic of BV. Our preliminary in vivo studies have demonstrated that non-lactobacillus bacteria Gardnerella vaginalis and Mobiluncus mulieris (CST-IV) changed inflammatory pathways, thereby suggesting G. vaginalis and M. mulieris may promote papillomavirus persistence in the genital tract. We hypothesize that papillomavirus co-infection with BV- associated bacteria promotes viral persistence and genital mucosal dysplasia. To test our hypothesis, we will use our novel mouse papillomavirus and vaginal bacterial infection models to 1) determine the changes of endogenous vaginal microbiota that are associated with high vaginal dysplasia in both immunocompromised and immunocompetent mice (Aim 1); 2) determine the interaction between BV-associated bacteria and metabolites and papillomavirus associated tumor progression (Aim 2). This is the first such study in both the microbiome and papillomavirus fields. Our findings will shed light on an understudied yet significant problem in cervical cancer development that is relevant to humans.