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

细菌性阴道病相关细菌在乳头瘤病毒持续存在和癌症中的作用

• 批准号: 10577870
• 负责人: Jiafen Hu
• 金额: $ 20.62万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577870
• 关键词: Address; Bacteria; Bacterial Infections; Bacterial Vaginosis; Biological Assay; Cancer Etiology; Caustics; Characteristics; Communicable Diseases; Communities; Data; Development; Disease; Disease Progression; Dysplasia; Environment; Female; Foundations; Funding; Gardnerella vaginalis; Genetic; Genital; Genitalia; Grant; Harvest; Health; Histologic; Histology; Human; Human Papilloma Virus Vaccine; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Immune response; Immunocompetent; Immunocompromised Host; Immunologics; Immunology; Immunosuppressive Agents; Individual; Infection; Inflammatory; International; Intervention; Irrigation; Kinetics; Knowledge; Lactobacillus; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mobiluncus mulieris; Modeling; Monitor; Mucous Membrane; Mus; Neoplasms; Observational Study; Pap smear; Papillomavirus; Papillomavirus Infections; Pathway interactions; Patients; Play; Population; Prevalence; RNA, Ribosomal, 16S; Reproduction; Research; Research Personnel; Research Project Grants; Role; Sexually Transmitted Diseases; Testing; Time; Tissues; Vaccinated; Vaccines; Vagina; Viral; Virus Diseases; Woman; bacterial metabolism; co-infection; curative treatments; effective therapy; experimental study; in vivo; malignant oropharynx neoplasm; microbial; microbiome; microbiome research; mouse model; novel; novel diagnostics; novel therapeutic intervention; reproductive tract; tumor progression; vaginal microbiota; virology

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.

抽象的 HPV是全球最常见的性传播疾病之一，是大约的生殖器因素 所有人类癌症中有5％。大多数宫颈癌（> 96％）和口咽癌（70％）的病例是 尽管当前的HPV疫苗已经成功降低了患病率 疫苗接种组覆盖的HPV类型，疫苗未覆盖的HPV类型的患病率仍然很高。 目前，数百万患有HPV感染的人没有现代治疗。我们的 拟议的研究旨在解决Par-20-061中提出的知识差距，以理解“共同的作用 癌症病因和进展中的感染”。新兴的实验和观察性研究已有 证明阴道微生物群可能在与HPV相关的疾病进展中起关键作用。 我们建议测试几种新的假设，包括阴道细菌及其代谢物作为潜力 与人类宫颈癌的进展/回归有关的免疫调查的驱动因素或主管。 在健康的女性中，阴道微生物环境由乳杆菌种类，多数菌种主导 微生物组轮廓（CST-I）。几种非乳杆菌种，包括多生物微生物组谱 （CST -III和-IV）与HPV感染/持续性和肿瘤形成有关。 有趣的是，在阴道中具有相对较小的乳杆菌（CST-I）社区的人通常是 由非乳杆菌（CST-III和-IV）定植，该细菌是BV的特征。我们的初步体内 研究表明，非乳杆菌阴道菌和Mobiluncus mulieris （CST-IV）改变了炎症途径，从而表明阴道和穆利里氏菌可能会促进 生殖道中的乳头瘤病毒持久性。我们假设乳头瘤病毒与BV-共同感染 相关细菌促进病毒持久性和生殖粘膜发育异常。为了检验我们的假设，我们将 使用我们新颖的小鼠乳头瘤病毒和阴道细菌感染模型1）确定的变化 内源性阴道微生物群，这两种免疫功能低下都与高阴道发育不良有关 和免疫能力的小鼠（AIM 1）； 2）确定与BV相关细菌与 代谢物和乳头瘤病毒相关的肿瘤进展（AIM 2）。这是两者中的第一次这样的研究 微生物组和乳头状病毒场。我们的发现将阐明一个理解但重大的问题 与人有关的宫颈癌发展。