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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：
10192900
负责人：
MARILIA Isabel CASCALHO
金额：
$ 23.4万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192900
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.

摘要肠道细菌病原体深刻地影响儿童的健康和发育，特别是在发育中的儿童，国家我们出乎意料地发现，小鼠中tnfrsf 13 b的多态性决定了对一种肠道病原体，属于在发育过程中引起许多慢性肠道感染的有机体家族在发达国家，在较小的程度上。TNFRSF 13 B编码跨膜激活剂， CAML相互作用物（TACI），BAFF和APRIL的受体，其控制B淋巴细胞分化为浆细胞和大量抗原特异性免疫球蛋白（IG）的产生。我们最近发现，一个高度多态性的基因TNFRSF 13 B控制着对鼠流感的易感性。肠道病原体、C.啮齿类动物，EHEC和EPEC模型。tnfrsf 13 b等位基因如何控制易感性，抗性还不完全清楚，但我们的初步工作将这些特性与自然界的控制联系起来。伊加序列和生产。因此，来自野生型小鼠的天然伊加诱导C. rodentium 而tnfrsf 13 b突变体和-KO小鼠中的伊加则没有。是什么连接了常见的突变，伊加的性质和伊加独立因素对C.啮齿动物是一个中心目标，我们打算进行的研究。这项研究将确定tnfrsf 13 b错义突变如何控制伊加的不同特性。和其他特征的突变小鼠促进抵抗C.啮齿动物感染、发病机制和传播途径。我们还将研究野生型动物产生的“天然”伊加如何触发C。rodentium 通过探索Tn 5诱变的文库和由LER驱动的负选择标记，启动子开展本申请中提出的工作不仅会促进概念上的理解，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，还为开发预防或逆转破坏性影响的药物提供了特定的分子靶点肠道致病菌对脆弱个体的影响。