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.

总结 肺炎克雷伯菌（Kpn）是影响数百人的医疗保健相关感染的主要病原体 数以百万计的世界各地。血流Kpn感染是特别值得关注的，因为它们有助于高患者 死亡率，是一个重大的公共卫生负担。Kpn定殖于健康人和哺乳动物的胃肠道（GI）， 免疫力低下的人。在健康个体中，细菌可以破坏肠上皮表面， 进入循环系统，但很快被清除。在缺乏完全胜任的免疫系统的患者中，Kpn 会导致危及生命的全身感染我们迫切需要了解控制人口增长的因素。 Kpn从胃肠道传播到无菌部位。我们开发了一种自然获得Kpn GI的小鼠模型 定植，以确定病原体和宿主因子，调节收购，运输和传播。使用 在该小鼠模型中，我们发现B细胞在控制胃肠道细菌负荷，全身传播， and mortality.在这个建议中，我们将研究B细胞调节Kpn生长的机制。 胃肠道、易位和全身扩散。在目标1中，我们将研究：a）预先存在和Kpn的作用- 诱导的（适应性）粘膜和全身性抗体调节Kpn GI生长和传播，和B） 在B细胞缺陷小鼠中，生态失调在驱动未受抑制GI生长和传播中的影响。这项工作将 目标2中的创新技术方法将揭示瓶颈和人口， Kpn沿着从口到肠道到系统不育位点的路径所经历的动态在两种野生型中 和B细胞缺陷小鼠。在这里，我们将利用独特的条形码化Kpn群体与高- 分辨率测序，以确定易位事件的频率，扩展动力学和起源 在不同的组织部位和血液中建立种群。最终，这项工作有望揭示 B细胞在控制Kpn生长和在宿主内不同部位的传播中的重要性， 这种情况发生的机制。