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

人类阴道微生物群的紊乱可能会导致女性严重的并发症，如果怀孕， 新生儿目前，大约四分之一的女性经历阴道生态失调，这种情况的特点是缺乏 与健康相关的乳酸菌属和微生物的异质性聚生体的存在。 尽管临床研究发现乳酸杆菌占主导地位的阴道群落与 减少阴道感染，阴道微生物群在保护免受 致病生物的生长尚未被彻底研究。如果不了解保护性微生物和 导致阴道微生态失调的宿主因素，针对其他分类群症状性流入的抗生素治疗 不能有效预防感染复发。因此，有必要确定初始因素 从而增加阴道感染的易感性。本提案的总体目标是了解 阴道微生物群可以直接或间接地提供针对致病菌生长的保护的能力 改变局部免疫反应以抑制病原体定殖。把致病菌的减少 我们将描述阴道微生物群或免疫概况是否由局部因素形成， 肠道中的微生物和免疫过程。我们假设内源性阴道微生物群 足以确定对致病菌定植的易感性并形成局部免疫特征， 在体内平衡和阴道生态失调中。为了了解阴道微生物群对 向阴道生态失调的易感状态的转变以及增强免疫保护的能力， pathobiont outgrowth，我们将询问在体内和体外模型。具体来说，我们将确定微生物 和免疫因子介导对阴道生态失调相关致病菌的保护 利用反映人源化阴道的HMb小鼠模型， 以乳杆菌属（Lactobacillus spp.）我们将描述HMB小鼠的阴道微生物群，以了解该社区 动力学和组成通过纵向16 S rRNA基因测序。我们将使用迷你- 生物反应器体外培养阴道微生物，测试特定的细菌和代谢物， 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分泌物 微生物群对局部免疫功能的训练。最后，我们将产生gnotobiotic小鼠来解决 阴道微生物群和免疫系统是否受到肠道的影响，确定阴道微生物群和免疫系统的来源。 对感染的易感性最终，该提案旨在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人的培训，申请人将侧重于传播 科学知识的多样性。贝勒医学院是实现这一目标的最佳机构 由于申请人可以使用尖端的研究设施、基础和临床科学， 专家，以及专门的研究和职业导师。

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.