New requirements for immunity to parasitic pathogens - when vaccines work and why they fail

对寄生虫病原体免疫力的新要求 - 疫苗何时有效以及为何失败

基本信息

批准号：
9790921
负责人：
Kirk David Christian Jensen
金额：
$ 38.11万
依托单位：
UNIVERSITY OF CALIFORNIA, MERCED
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9790921
关键词：
A/J Mouse ATAC-seq Address Adoptive Transfer Affinity African Alleles Animals Antibodies Antibody Response Antigenic Variation Antigens B-Lymphocytes Binding Blood C57BL/6 Mouse CD19 gene Cell Lineage Cells Cellular Immunity ChIP-seq Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Complement DNA Data Defect Development Elements Epigenetic Process Epitopes Exhibits Failure Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Transcription Giardia Goals Grant Human Hydrofluoric Acid IgG3 Immune Immune Sera Immune system Immunity Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M Immunologic Memory Immunologics Immunology Inbred Mouse Knockout Mice Malaria prevention Maps Mediating Membrane Proteins Memory Methods Modeling Molecular Morbidity - disease rate Mus Natural Immunity Nature Nuclear Parasites Parasitic Diseases Parasitology Passive Immunization Plasmodium Play Population Predisposition Prevention Proteins Quantitative Trait Loci Recombinants Reporting Resistance Role Secondary to Serum Surface Surface Antigens T-Independent Antigens TP53 gene Toxoplasma gondii Toxoplasmosis Trypanosoma Vaccination Vaccines Variant Virulence Virulent Work adaptive immunity cell type epigenetic regulation experimental study genetic analysis genetic approach member novel pathogen prevent response secondary infection

项目摘要

PROJECT SUMMARY Immunological memory is the ability of our immune system to respond with greater strength and quickness upon re-encounter with the same pathogen (i.e. secondary infection). Immunological memory is the basis for vaccination which remains the most successful method for preventing infectious disease. Yet, a fully protective vaccine that prevents a single human parasitic disease has not been realized to date. Why is immunity to parasitic pathogens so difficulty to achieve? Our current work on secondary infections with the apicomplexan parasite, Toxoplasma gondii, suggest that failure of immunological memory responses is genetically determined. In this grant submission, we have used a forward genetic approach to uncover new requirements for host immunity to highly virulent strains T. gondii. Both genetic and immunological data converge on a B-1b cell population that is specifically expanded in resistant mice. This cell type represents a bridge between innate and adaptive immune immunity, which can recognize both self- and foreign- antigen. Our central hypothesis is that memory B-1 cells control resistance to challenge with virulent T. gondii strains, and this response is determined by allelic variation of Nfkbid. IκBNS, encoded by Nfkbid, is a member of the atypical nuclear regulators of NF-κB-dependent transcription. Nfkbid null mice fail to develop B-1 cells and antibody responses to T-independent antigens, and as reported here, have massive defects in producing T. gondii-specific antibodies. Experimental approaches from immunology, genetics and molecular parasitology will be used to address questions surrounding our central hypothesis. In Aim 1, adoptive transfer experiments will be performed to delineate protection conferred by the B-1 lineage and the functional quality of parasite-specific antibodies they produce. In Aim 2, epigenetic approaches are proposed to study the mechanism by which IκBNS mediates protective B cell responses during a secondary infection. In Aim 3, we will explore whether antibody responses directed against GPI-moieties on T. gondii surface antigens explain parasite strain-differences in secondary infection virulence. Antigenic variation is the major mechanism by which protozoan pathogens such as African Trypanosomes, Plasmodium sp. and Giardia evade B cell- mediated antibody responses. Surface antigens of T. gondii are highly polymorphic. Immunity conferred by B-1 cells may depend on their ability to produce antibodies that recognize broadly conserved epitopes within variable surface antigens. Eliciting this response during vaccination could have major bearing on the prevention of human parasitic disease.

项目概要免疫记忆是我们的免疫系统以更强的力量和更快的速度做出反应的能力再次遇到相同的病原体（即继发感染）是免疫记忆的基础。疫苗接种仍然是预防传染病最成功的方法，也是一种完全保护性的方法。迄今为止尚未实现预防单一人类寄生虫病的疫苗。我们目前对继发感染的工作这么难实现吗？顶复门寄生虫，弓形虫，表明免疫记忆反应失败是在本次拨款申请中，我们使用了正向遗传方法来发现新的。宿主对高毒力弓形虫菌株免疫的要求遗传和免疫学数据。聚集在抗性小鼠中专门扩增的 B-1b 细胞群上。先天免疫和适应性免疫之间的桥梁，可以识别自身和外来免疫我们的中心假设是，记忆 B-1 细胞控制着对有毒 T 攻击的抵抗力。弓形虫菌株，这种反应是由 Nfkbid 编码的 Nfkbid 等位基因变异决定的。是 NF-κB 依赖性转录的非典型核调节因子的成员，Nfkbid 缺失小鼠无法表达。开发 B-1 细胞和针对 T 独立抗原的抗体反应，正如此处报道的，具有大量免疫学、遗传学和免疫学实验方法在生产弓形虫特异性抗体方面存在缺陷。分子寄生虫学将用于解决围绕我们的中心假设的问题。将进行收养转移实验来描绘 B-1 谱系和在目标 2 中，提出了表观遗传学方法来提高它们产生的寄生虫特异性抗体的功能质量。研究 IκBNS 在继发感染期间介导保护性 B 细胞反应的机制。目标 3，我们将探讨抗体反应是否针对弓形虫表面抗原上的 GPI 部分解释寄生虫毒株继发感染毒力的差异是主要机制。非洲锥虫、疟原虫和贾第鞭毛虫等原生动物病原体可以逃避 B 细胞。 B-1 介导的抗体反应具有高度多态性。细胞可能依赖于它们产生抗体的能力，这些抗体识别体内广泛保守的表位在疫苗接种过程中引发这种反应可能会对疫苗接种产生重大影响。预防人类寄生虫病。