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

• 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
• 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

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.

项目摘要 免疫记忆是我们的免疫系统以更大的强度和速度做出反应的能力 再次遇到相同的病原体时（即继发感染）。免疫记忆是 疫苗接种仍然是预防传染病最成功的方法。然而，一个全面的保护 迄今为止，还没有实现预防单一人类寄生虫病的疫苗。为什么豁免权 寄生病原体那么难实现？我们目前对继发性感染的研究 顶复体寄生虫，刚地弓形虫，表明免疫记忆反应的失败， 基因决定的。在这次拨款申请中，我们使用了一种正向遗传学方法来发现新的 宿主对强毒株T.刚地。遗传学和免疫学数据 集中于在抗性小鼠中特异性扩增的B-1 B细胞群。此细胞类型代表 先天免疫和适应性免疫之间的桥梁，它可以识别自身和外源免疫， 抗原的我们的中心假设是记忆B-1细胞控制对毒性T细胞攻击的抗性。 弓形虫菌株，这种反应是由Nfkbid的等位基因变异决定的。IκBNS，由Nfkbid编码， 是NF-κ B依赖性转录的非典型核调节因子。Nfkbid无效小鼠不能 发展B-1细胞和对T-非依赖性抗原的抗体应答，并且如本文所报道的， T. gondii特异性抗体。来自免疫学、遗传学和 分子寄生虫学将被用来解决围绕我们的中心假设的问题。在目标1中， 将进行过继转移实验以描述由B-1谱系赋予的保护作用， 它们产生的寄生虫特异性抗体的功能质量。在目标2中，提出了表观遗传方法， 研究IκBNS介导二次感染期间保护性B细胞应答的机制。在 目的3，我们将探讨是否有针对T。弓形虫表面抗原 解释寄生虫株在二次感染毒力上的差异。抗原变异是主要机制 原生动物病原体如非洲锥虫、疟原虫属和贾第虫通过这种途径逃避B细胞， 介导的抗体应答。T.弓形虫是高度多态的。B-1赋予的豁免 细胞可能依赖于它们产生抗体的能力，这些抗体识别细胞内广泛保守的表位， 可变表面抗原在接种疫苗期间引起这种反应可能对免疫系统产生重大影响。 预防人体寄生虫病。