The Microbiome as a risk factor for hr-HPV persistence and Cervical Cancer

项目总结 宫颈癌(CC)是全球第四大常见女性恶性肿瘤。死亡率是现在的三倍 拉丁美洲和加勒比海地区比美国高，波多黎各(PR)最高 尽管接种了疫苗，但美国宫颈癌的年龄调整发病率。持续感染高危人群 人乳头瘤病毒(hr-HPV)类型是导致宫颈癌的必要条件，但还不足以引起宫颈癌。其他尚待解决 未知的辅助因子是促进HR-HPH持续和进展为癌症所必需的，然而这些 这些途径还没有完全被理解。除了HPV感染，促进癌症的关键因素 进展可能存在于宫颈环境中，特别是其局部微生物群。初步证据 表明细菌多样性的增加和乳酸菌的减少与高等级有关 然而，鳞状上皮内病变(HSIL)，除了我们小组研究的初步数据 宫颈酵母菌，我们还没有了解到真菌群落与其他组合的重要性 代谢和宿主因素对疾病进展的影响。在这里，我们建议全面研究病毒-- 使用最先进的测序技术和新的生物信息学算法，微生物群与宿主的相互作用 为了应对一种以美国和全球健康差距为特征的恶性肿瘤。我们最重要的是 目的是确定控制人类乳头状瘤病毒持续存在的微生物种间相互作用和宿主因素。 和宫颈疾病。我们将利用已经从300多名参与者那里收集的样本和数据 横断面先导性研究队列，并另外选择200名参与者进行纵向随访。 在目标1中，我们将量化宫颈阴道细菌和真菌群落的组成和代谢组 从横断面上区分患有或不伴有宫颈发育不良和存在或不存在高危的妇女 (HR)HPV。在目标2中，我们将鉴定细菌和真菌菌株、功能基因途径和代谢产物 在纵向时间序列上区分没有宫颈疾病的妇女(NILM-HPV阴性和低风险)， 从感染HPV的高危女性发展到高度不典型增生。拥有鸟枪式元基因组学数据 从纵向上选择患者是唯一能够了解基因和功能变化的关键 分类群，以告知它们在进化或退化中的作用。我们假设将会有基因组细菌 区分无病变和有宫颈疾病的妇女的菌株，以及多水平的组学数据， 包括微生物组、代谢组和细胞因子图谱的预测价值可能比 仅有HPV风险。这项工作将为一个长期存在的核心问题提供一个强有力的平台 并将为阐明其发病机制奠定基础。 微生物群影响HPV的持久性和异型增生。

PROJECT SUMMARY Cervical cancer (CC) is the fourth most common female malignancy worldwide. Mortality rates are three times higher in Latin America and the Caribbean than in the United States, and Puerto Rico (PR) has the highest age-adjusted incidence for cervical cancer in the US despite of vaccination. Persistent infection with high-risk human papilloma virus (hr-HPV) types is a necessary, but not sufficient to cause cervical cancer. Other yet unknown cofactors are required to promote hr-HPH persistence and progression to cancer, however these pathways are not completely understood. Besides HPV infections, the key factors that promote cancer progression likely reside in the cervical environment, notably its local microbiome. Preliminary evidence suggests that increased bacterial diversity and reduction in Lactobacillus are associated with High grade squamous intraepithelial lesion (HSIL), however, except for preliminary data from our group that studied cervical yeast, we have not yet understood the importance of the fungal communities and other combined metabolic and host factors on disease progression. Here we propose to comprehensively study virus- microbiota-host interactions, using state of the art sequencing technologies and novel bioinformatic algorithms to address a malignancy, that is characterized by health disparities in the US and globally. Our overarching goal is to identify microbial inter-species interactions and host factors that control hr-HPV persistence and cervical disease. We will leverage samples and data already collected from over 300 participants in a cross-sectional pilot study cohort, and to additionally select 200 participants to follow up longitudinally. In Aim 1, we will quantify the cervicovaginal bacterial and fungal community composition and metabolome cross-sectionally, differentiating women with or without cervical dysplasia and presence or absence of high risk (hr) HPV. In Aim 2 we will identify bacterial and fungal strains, functional gene pathways and metabolites that over a longitudinal timeseries distinguish women without cervical disease (NILM - HPV negative and low-risk), from high-risk HPV infected women who progress to high grade dysplasia. Having shotgun metagenomics data from selected patients longitudinally is unique to be able to understand gene and functional changes of key taxa to inform on their role in progression or regression. We hypothesize that there will be genomic bacterial strains that differentiate women without lesions and with cervical disease and that multiple levels of omics data, including the microbiome, the metabolome and the cytokine profiles may have higher predictive value than HPV risk alone. This work will develop a strong platform for a long standing and central question regarding cervical disease in Hispanics and will lay the foundation for elucidating the mechanisms by which microbiomes affect HPV persistence and dysplasia.