Determining the role of the vaginal microbiota in microbial and immunological resistance to vaginal pathobiont colonization

人体阴道微生物区系紊乱会给女性带来严重的并发症，如果怀孕，还会导致她们的 新生儿。目前，大约四分之一的女性经历了阴道生物失调，这种情况的标志是缺乏 与健康相关的乳杆菌属，以及异质微生物群的存在。 尽管临床研究发现乳杆菌优势阴道菌群与 减少阴道感染，阴道微生物区系在预防感染中发挥的作用的复杂性 病原体的生长还没有得到彻底的研究。不了解保护性微生物和 导致阴道生物失调的宿主因素，针对其他类群有症状的涌入的抗生素治疗 在预防感染复发方面效果不佳。因此，有必要定义初始因素 这会增加对阴道感染的易感性。这项建议的首要目标是理解 阴道微生物区系可以直接或间接提供对病原体生长的保护的能力 改变局部免疫反应，抑制病原体定植。归因于病原体的减少 定植到局部因素，我们将描绘出阴道微生物区系或免疫图谱是否由 肠道中的微生物和免疫过程。我们假设内源性阴道微生物区系是 足以确定对致病细菌定植的敏感性并塑造局部免疫状况 在动态平衡和阴道生物失调方面。为了了解阴道微生物区系对 过渡到阴道生物失调的易感状态和增强免疫保护能力 对于病原体的生长，我们将询问体内和体外的模型。具体地说，我们将确定微生物 以及介导对B组阴道生物失调相关致病菌的保护作用的免疫因素 利用HMBb小鼠模型，反映人源化阴道的链球菌和普氏杆菌 以乳杆菌属为优势种。我们将描述HMB小鼠的阴道微生物区系，以了解群落 16S rRNA基因纵向测序的动态和组成。然后我们将雇用迷你- 生物反应器在体外培养阴道微生物，测试特定的细菌和代谢产物，能够 限制阴道感染。此外，我们将利用流式细胞术来阐明不同的阴道 微生物区系对局部免疫功能有训练作用。最后，我们将生成灵芝小鼠来解决 肠道是否影响阴道微生物区系和免疫系统，确定阴道来源 易受感染。最终，这项提议寻求通过以下方式使科学界代表性不足的群体受益 对妇女健康的治疗发现和对申请者的培训，申请者将侧重于传播 科学知识传授给不同的人群。贝勒医学院是实现这一目标的最佳机构 因为申请者可以获得尖端的研究设施、基础和临床科学 专家，以及专注的研究和职业指导。

Disturbances of the human vaginal microbiota can cause severe complications for women and, if pregnant, their neonates. Currently, about one in four women experience vaginal dysbiosis, a condition marked by the absence of the health-associated genus Lactobacillus and the presence of a heterogenous consortium of microbes. Although clinical studies have found associations between Lactobacillus dominant vaginal communities and reduced vaginal infection, the complexity of the role that vaginal microbiota play in the protection against pathobiont outgrowth has not been thoroughly studied. Without an understanding of protective microbial and host factors leading into vaginal dysbiosis, antibiotic therapeutics targeting the symptomatic influx of other taxa have not been effective in preventing the recurrence of infection. Thus, it is necessary to define the initial factors that increase susceptibility to vaginal infection. The overarching goal of this proposal is to understand the capacity at which the vaginal microbiota can directly confer protection against pathobiont outgrowth or indirectly alter the local immune response to inhibit pathobiont colonization. To attribute a reduction of pathobiont colonization to local factors, we will delineate whether the vaginal microbiota or immune profile are shaped by microbial and immunological processes in the gut. We hypothesize that endogenous vaginal microbiota are sufficient to determine susceptibility to pathobiont colonization and shape the local immune profile both in homeostasis and in vaginal dysbiosis. To understand both the vaginal microbiota’s influence on the transition to the susceptible state of vaginal dysbiosis and the ability to enhance immunological protection against pathobiont outgrowth, we will interrogate in vivo and in vitro models. Specifically, we will determine the microbe and immune factors that mediate protection against vaginal dysbiosis-associated pathobionts Group B Streptococcus and Prevotella bivia by utilization of the HMbmice model, which reflects a humanized vaginal tract dominated by Lactobacillus spp. We will describe the vaginal microbiota of HMbmice to understand the community dynamics and compositions through longitudinal 16S rRNA gene sequencing. We will then employ mini- bioreactors to cultivate vaginal microbes in vitro, testing for specific bacteria and metabolites that are capable of limiting vaginal infection. Additionally, we will utilize flow cytometry to elucidate the impact that different vaginal microbiota have on training of the local immune function. Lastly, we will generate gnotobiotic mice to resolve whether the vaginal microbiota and immune system are influenced by the gut, establishing the source of vaginal susceptibility to infection. Ultimately, this proposal seeks to benefit underrepresented groups in science through the therapeutic discoveries for women’s health and the training of the applicant, who will focus on disseminating scientific knowledge to a diverse population. Baylor College of Medicine is the optimal institution for the fulfillment of this proposal because of the applicant’s access to cutting-edge research facilities, basic and clinical science experts, and dedicated research and career mentorship.