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.

抽象的肠细菌病原体对儿童的健康和发展产生深远影响，尤其是在发展国家。我们出乎意料地发现，小鼠中TNFRSF13B的多态性确定了对属于生物家庭的肠道病原体，引起许多慢性启动子感染的发育国家，在发达地区的范围较小。 TNFRSF13B编码跨膜激活剂和 CAML Intercontor（TACI）是BAFF和APRIP的接收器，该接收器控制B淋巴细胞的分化血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，高度多态基因TNFRSF13B控制着对鼠的敏感性肠病，啮齿动物C. rodentium，对EHEC和EPEC进行了建模。 TNFRSF13B等位基因如何控制易感性与阻力是不完全理解的，但是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。那是野生型小鼠的天然IgA影响啮齿动物的表达病毒基因，而TNFRSF13B突变剂和-KO小鼠中的IgA却没有。是什么联系共同突变， IgA和IgA独立因素对易感性或抗啮齿动物的抗性的特性是一个中心目标我们建议进行的研究。提出的研究将确定如何控制IgA不同特性的TNFRSF13B错义突变突变小鼠的其他特征促进了对啮齿动物念珠菌感染，发病机理和传播的抗性。我们还将研究WT动物产生的“天然” IgA如何触发啮齿动物的转录病毒基因通过探索带有否定性标记驱动器的TN5-ratagenizatization库发起人。在此应用程序中进行提出的工作不仅会提高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，它可能还提供特定的分子靶标，用于开发试剂以防止或逆转破坏性影响对脆弱个体的肠病细菌的。