Role of B cells in controlling Klebsiella pneumoniae associated disease states

B 细胞在控制肺炎克雷伯菌相关疾病状态中的作用

• 批准号: 10731411
• 负责人: Karen M Haas
• 金额: $ 19.38万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-25 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731411
• 关键词: Affect; Animal Model; Antibiotic Resistance; Antibiotics; Antibodies; Automobile Driving; B-Lymphocytes; Bacteria; Bar Codes; Blood; Blood Circulation; Cardiovascular system; Complement; Data; Development; Disease; Disease Progression; Epithelium; Event; Exhibits; Feces; Frequencies; Gastrointestinal tract structure; Growth; Health; Host resistance; Hour; Human; Immune; Immune system; Immunocompetent; Immunocompromised Host; Immunoglobulins; Immunologic Deficiency Syndromes; Individual; Infection; Integration Host Factors; Intervention; Klebsiella pneumoniae; Knowledge; Life; Liver; Mediating; Modeling; Molecular; Mucous Membrane; Mus; Oral cavity; Organ; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Polymeric Immunoglobulin Receptors; Population; Population Dynamics; Predisposition; Prevention; Prevention strategy; Probiotics; Public Health; Publishing; Resistance; Resolution; Role; Sampling; Sepsis; Site; Spleen; Sterility; Surface; Systemic infection; Therapeutic Intervention; Time; Tissues; Wild Type Mouse; Work; colonization resistance; combat; deep sequencing; disorder control; dysbiosis; epidemiologic data; experience; experimental study; gastrointestinal; gut colonization; gut microbiome; healthcare-associated infections; host microbiota; humoral immunity deficiency; improved; innovation; intestinal epithelium; microbiome; mortality; mouse model; pathogen; prevent; reconstitution; resistant Klebsiella pneumoniae

SUMMARY Klebsiella pneumoniae (Kpn) is a primary causative agent of healthcare-associated infections affecting hundreds of millions worldwide. Bloodstream Kpn infections are of particular concern as they contribute to high patient mortality and represent a major public health burden. Kpn colonizes the gastrointestinal (GI) tract of healthy and immunocompromised individuals. In healthy individuals, bacteria can breach the intestinal epithelial surface and enter the circulatory system, but are rapidly cleared. In patients lacking a fully competent immune system, Kpn can cause life-threatening systemic infections. There is an urgent need to understand the factors that control the spread of Kpn from the GI tract to sterile sites. We developed a mouse model of naturally acquired Kpn GI colonization to identify pathogen and host factors which regulate acquisition, carriage, and dissemination. Using this mouse model, we found a critical role for B cells in controlling GI bacterial burden, systemic dissemination, and mortality. In this proposal, we will investigate the mechanisms by which B cells regulate Kpn growth in the GI tract, translocation, and systemic spread. In Aim 1, we will examine: a) the roles of pre-existing and Kpn- induced (adaptive) mucosal and systemic antibody in regulating Kpn GI growth and dissemination and b) the impact of dysbiosis in driving unchecked GI growth and dissemination in B cell-deficient mice. This work will be complemented by an innovative technical approach in Aim 2 which will reveal bottlenecks and population dynamics experienced by Kpn along the path from the mouth to the gut to systemic sterile sites in both wild type and B cell-deficient mice. Here we will leverage a uniquely barcoded Kpn population in combination with high- resolution sequencing to identify frequencies of translocation events, expansion dynamics, and the origination of founding populations within distinct tissue sites and blood. Ultimately, this work is expected to reveal the importance of B cells in controlling Kpn growth and dissemination at various sites within the host and the mechanisms by which this occurs.

概括 肺炎克雷伯菌（KPN）是影响数百种的医疗相关感染的主要病因 全球数百万。血流KPN感染特别关注，因为它们有助于高患者 死亡率并代表着重大的公共卫生负担。 KPN在健康和 免疫功能低下的个体。在健康的个体中，细菌可以违反肠上皮表面和 输入循环系统，但已迅速清除。在缺乏完全有能力的免疫系统的患者中，KPN 可能引起威胁生命的全身感染。迫切需要了解控制的因素 KPN从胃肠道传播到无菌地点。我们开发了一种自然获得的kpn gi的鼠标模型 定植以识别调节获取，运输和传播的病原体和宿主因素。使用 这种小鼠模型，我们发现B细胞在控制GI细菌负担，全身传播， 和死亡率。在此提案中，我们将研究B细胞调节KPN生长的机制 胃肠道，易位和全身传播。在AIM 1中，我们将研究：a）现有和kpn-的作用 诱导（自适应）粘膜和全身性抗体调节KPN GI生长和传播，b） 营养不良对B细胞缺陷小鼠不受检查的GI生长和传播的影响。这项工作将是 AIM 2中的一种创新技术方法补充，该方法将揭示瓶颈和人口 KPN沿着从嘴到肠道到全身无菌位点的路径经历的动力学 和B细胞缺陷的小鼠。在这里，我们将利用独特的条形码KPN人群，并结合高级 分辨率测序以识别易位事件，扩展动力学和起源的频率 在不同组织部位和血液中的基础种群。最终，这项工作有望揭示 B细胞在控制宿主和宿主内部各个地点的KPN生长和传播方面的重要性 发生这种情况的机制。