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

确定阴道微生物群在微生物和免疫学抵抗阴道病原体定植中的作用

基本信息

批准号：
10725121
负责人：
Marlyd Elizabeth Mejia
金额：
$ 4.77万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-26 至 2025-08-25
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725121
关键词：
16S ribosomal RNA sequencing Address Aerobic Antibiotics Bacteria Bacterial Vaginosis Basic Science Bioreactors Caring Categories Cells Clinical Clinical Research Clinical Sciences Communities Dedications Diagnosis Disease Environmental Risk Factor Estrus Exhibits Female Flow Cytometry Genitourinary system Gnotobiotic Goals Health Homeostasis Human Immune Immune response Immune system Immunity Immunologic Factors Immunologics In Vitro Incidence Infection Infection Control Inflammatory Response Institution Integration Host Factors Investigation Knowledge Lactobacillus Mediating Mediation Medicine Mentorship Microbe Modeling Mus Observational Study Organ Play Population Population Heterogeneity Predisposition Prevotella Process Property Recurrence Regimen Research Resistance Ribosomal DNA Role Sampling Science Shapes Site Source Streptococcus Group B Swab Symptoms T-Lymphocyte Testing Therapeutic Time Tissues Training Underrepresented Populations United States Vagina Vaginitis Woman Women&apos s Health career college disorder risk dysbiosis experience gut microbiota immune cell infiltrate immune function immune resistance improved in vitro Model in vivo microbial microbial community microbial composition microbial signature microbiota microorganism mouse model neonate neutrophil pathobiont pathogen permissiveness pregnant prevent prophylactic recurrent infection reproductive research facility response therapeutic target tool development vaginal infection vaginal microbiome vaginal microbiota

项目摘要

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.

人类阴道菌群的障碍会给女性带来严重的并发症，如果怀孕，新生儿。目前，大约四分之一的女性患阴道营养不良，这种状况以缺席为标志与健康相关的乳杆菌属和微生物异质联盟的存在。尽管临床研究发现乳杆菌主要的阴道群落与阴道感染减少，阴道微生物群在保护中的作用的复杂性 Pathobiont的生长尚未彻底研究。没有了解保护性微生物和导致阴道营养不良的宿主因素，针对其他类群的症状影响的抗生素疗法没有有效防止感染的复发。那是有必要定义初始因素这增加了对阴道感染的敏感性。该提议的总体目标是了解阴道微生物群可以直接赋予病原体生长或间接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，我们将描述阴道微生物群或免疫轮廓是由肠道中的微生物和免疫学过程。我们假设内源性阴道菌群是足以确定病原体定殖的易感性并塑造局部免疫特征在体内稳态和阴道营养不良中。了解阴道微生物群对过渡到易感的阴道营养不良状态，并能够增强免疫学保护的能力 Pathobiont的生长，我们将在体内和体外模型中询问。具体而言，我们将确定微生物和免疫因素介导对阴道营养不良相关的病原体的保护通过利用HMBMICE模型，链球菌和Prevotella bivia，反映了人源性阴道由乳杆菌属于植物。我们将描述HMBMICE的阴道菌群，以了解社区通过纵向16S rRNA基因测序的动力学和组成。然后，我们将员工迷你生物反应器在体外培养阴道微生物，测试特定细菌和代谢物的能力限制阴道感染。此外，我们将利用流式细胞仪来阐明不同阴道的影响微生物群对局部免疫功能进行训练。最后，我们将生成gnotobiotic小鼠解决阴道菌群和免疫系统是否受肠道影响，建立阴道的来源感染的敏感性。最终，该提案试图通过妇女健康的治疗发现和申请人的培训，她们将专注于传播对潜水员人口的科学知识。贝勒医学院是履行的最佳机构该建议是因为申请人获得了尖端研究设施，基础和临床科学专家，敬业的研究和职业心态。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vaginal microbial dynamics and pathogen colonization in a humanized microbiota mouse model.

DOI：
10.1038/s41522-023-00454-9
发表时间：
2023-11-20
期刊：
NPJ BIOFILMS AND MICROBIOMES
影响因子：
9.2
作者：
Mejia, Marlyd E.;Mercado-Evans, Vicki;Zulk, Jacob J.;Ottinger, Samantha;Ruiz, Korinna;Ballard, Mallory B.;Fowler, Stephanie W.;Britton, Robert A.;Patras, Kathryn A.
通讯作者：
Patras, Kathryn A.