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

摘要 肠道致病菌深刻影响着儿童的健康和发育，尤其是在发育中 国家。我们出人意料地发现，小鼠中TNFRSF13B的多态性决定了对An的抵抗力 一种肠道病原体，属于一类生物体，在发育过程中引起大部分慢性肠道感染 在发达国家，在较小程度上也是如此。TNFRSF13B编码跨膜激活剂和 CAM1相互作用蛋白(TACI)，BAFF和APRIL的受体，调控B淋巴细胞分化为 浆细胞和产生大量的抗原特异性免疫球蛋白(Ig)。 我们最近发现，一种高度多态的基因TNFRSF13B控制着对一只小鼠的易感性 肠道病原体，玫瑰冠状芽孢杆菌，模拟EHEC和EPEC。TNFRSF13B等位基因如何控制易感性与 抗性尚不完全清楚，但我们的初步工作将这些特性与自然的控制联系起来 免疫球蛋白A序列和生产。因此，野生型小鼠的天然免疫球蛋白A诱导轮状芽胞杆菌的表达 毒力基因，而在TNFRSF13B突变和-KO小鼠中的IgA没有。是什么将常见的突变联系在一起， 对轮状芽胞杆菌敏感或耐药的IgA和IgA非依赖性因素的特性是一个中心目标 我们计划进行的研究。 提出的研究将确定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轮状芽胞杆菌感染、发病和传播的抵抗力。 我们还将研究WT动物产生的天然免疫球蛋白A如何触发轮状芽孢杆菌的转录 通过探索带有LER驱动的负选择标记的Tn5诱变文库的毒力基因 推动者。执行本申请中提出的工作不仅将促进概念上的理解 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，它可能 还为开发试剂提供特定的分子靶点，以防止或逆转毁灭性的影响 肠道致病细菌在易受感染的个体身上。

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.