TNRSF13B polymorphisms and the control of innate B cell responses – a double edged sword

TNRSF13B 多态性和先天 B 细胞反应的控制——一把双刃剑

基本信息

批准号：
10330588
负责人：
MARILIA Isabel CASCALHO
金额：
$ 19.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-19 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330588
关键词：
Alleles Animal Model Animals Antigens B cell differentiation B-Lymphocytes Bacteria Binding CAMLG gene Cessation of life Child Child Development Childhood Chronic Citrobacter rodentium Code Country Defect Detection Developing Countries Development Diarrhea Disease Dominant-Negative Mutation Elements Enteral Enterobacteriaceae Equilibrium Escherichia coli Escherichia coli EHEC Evolution Family Frequencies Genes Genetic Polymorphism Genetic Transcription Goals Growth Health Homologous Gene Human Immune response Immune system Immunity Immunoglobulin A Immunoglobulins Impaired cognition Individual Infection Infection Control Infectious Agent Inherited Knockout Mice Libraries Malnutrition Manuscripts Mediating Missense Mutation Modeling Molecular Target Mus Mutant Strains Mice Mutation Natural Immunity Organism Pathogenesis Pathogenicity Plasma Cells Predisposition Production Property Recurrence Regulation Research Resistance Resistance development Signal Induction Signal Transduction Structure Testing Therapeutic Vaccines Variant Virulence Vulnerable Populations Wild Type Mouse Work adaptive immune response adaptive immunity antimicrobial cognitive development enteric infection enteric pathogen enteropathogenic Escherichia coli genetic variant human model improved microbial mouse model mutant novel novel strategies pathogenic bacteria prevent programs promoter receptor resistance mechanism response transmission process

项目摘要

Abstract Enteric bacterial pathogens profoundly impact the health and development of children, especially in developing countries. We unexpectedly discovered that polymorphisms of tnfrsf13b in mouse determine resistance to an enteric pathogen that belongs to a family of organisms that cause much of chronic enteric infection in developing countries, and to a lesser extent in developed regions. TNFRSF13B encodes the Transmembrane Activator and CAML interactor (TACI), the receptor for BAFF and APRIL, that governs differentiation of B lymphocytes into plasma cells and production of large amounts of antigen-specific immunoglobulin (Ig). We recently discovered that a highly polymorphic gene, TNFRSF13B controls susceptibility to a murine enteropathogen, C. rodentium, that models EHEC and EPEC. How tnfrsf13b alleles govern susceptibility versus resistance is incompletely understood but our preliminary work connects these properties to the control of natural IgA sequences and production. Thus, natural IgA from wild type mice induces expression of C. rodentium virulence genes whereas IgA in tnfrsf13b-mutant and -KO mice does not. What connects the common mutations, properties of IgA and IgA independent factors to susceptibility or resistance to C. rodentium is a central goal the research we propose to conduct. The research proposed will determine how tnfrsf13b missense mutations controlling distinct properties of IgA and other features of mutant mice promote resistance to C. rodentium infection, pathogenesis and transmission. We will also investigate how “natural” IgA produced by WT animals triggers the transcription of C. rodentium virulence genes by exploring a Tn5-mutagenized library with a negatively selectable marker driven by the ler promoter. Conducting the work proposed in this application will not only advance conceptual understanding about the co-evolution of the mammalian immune system and an important class of enteric pathogens, it may also provide specific molecular targets for development of agents to prevent or reverse the devastating impact of enteropathogenic bacteria on vulnerable individuals.

抽象的肠道细菌病原体深刻影响儿童的健康和发育，尤其是发育中的儿童。我们意外地发现小鼠体内 tnfrsf13b 的多态性决定了对某种药物的抵抗力。肠道病原体属于导致发育中大部分慢性肠道感染的生物体家族 TNFRSF13B 编码跨膜激活剂和 CAML 相互作用蛋白 (TACI)，BAFF 和 APRIL 的受体，控制 B 淋巴细胞分化为浆细胞并产生大量抗原特异性免疫球蛋白（Ig）。我们最近发现高度多态性基因 TNFRSF13B 控制着小鼠对肠道病原体，啮齿类动物，模拟 EHEC 和 EPEC tnfrsf13b 等位基因如何控制易感性。抵抗力尚不完全清楚，但我们的初步工作将这些特性与自然的控制联系起来 IgA 序列和生产因此，来自野生型小鼠的天然 IgA 诱导 C. rodentium 的表达。毒力基因，而 tnfrsf13b 突变和 KO 小鼠中的 IgA 则没有。 IgA 的特性和 IgA 独立因素对 C. rodentium 的易感性或抗性是一个中心目标我们建议进行的研究。拟议的研究将确定 tnfrsf13b 错义突变如何控制 IgA 的不同特性突变小鼠的其他特征促进了对啮齿类柠檬酸杆菌感染、发病机制和传播的抵抗力。我们还将研究 WT 动物产生的“天然”IgA 如何触发 C. rodentium 的转录通过探索具有由 ler 驱动的负选择标记的 Tn5 诱变文库来研究毒力基因开展本申请中提出的工作不仅会促进概念理解。关于哺乳动物免疫系统和一类重要的肠道病原体的共同进化，它可能还为药物开发提供具体的分子靶标，以防止或扭转破坏性影响脆弱个体上的肠道致病细菌。