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: 10227131
• 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/10227131
• 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; Wild Type Mouse; 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.

项目总结 免疫记忆是我们的免疫系统以更强大和更快的速度做出反应的能力 当再次遇到相同的病原体(即二次感染)时。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，一个完全保护性的 到目前为止，还没有实现预防单一人类寄生虫病的疫苗。为什么免疫被认为是 寄生病原体这么难做到？我们目前在继发性感染方面的工作是通过 顶端复合体寄生虫弓形虫提示免疫记忆反应的失败是 基因决定的。在这份拨款申请中，我们使用了一种正向遗传方法来发现新的 对强毒株弓形虫的宿主免疫要求。遗传和免疫学数据 聚集在B-1b细胞群上，这种细胞群是在耐药小鼠中特异扩增的。此单元格类型表示 先天免疫和获得性免疫之间的桥梁，它可以识别自体和异体- 抗原。我们的中心假设是记忆B-1细胞控制对毒力T。 这种反应是由Nfkid的等位基因变异决定的。IκBNS，由NFKBID编码， 是核转录因子κB依赖的非典型核调控因子的一员。Nfkid基因缺失的小鼠未能 发展B-1细胞和对T非依赖性抗原的抗体反应，正如这里报道的那样，有大量的 生产弓形虫特异性抗体的缺陷。免疫学、遗传学和生物科学的实验方法 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， 将进行采用转移实验，以描绘B-1血统和 它们产生的寄生虫特异性抗体的功能质量。在目标2中，提出了表观遗传学方法来 研究IκBNS在继发感染期间介导保护性B细胞反应的机制。在……里面 目的3，我们将探索针对弓形虫表面抗原的gpi部分的抗体反应。 解释寄生虫菌株在二次感染毒力上的差异。抗原性变异是主要机制 原生动物病原体如非洲锥虫、疟原虫等。贾第虫逃避B细胞- 介导的抗体反应。弓形虫表面抗原具有高度的多态。B-1赋予的豁免权 细胞可能取决于它们产生抗体的能力，这些抗体识别 可变表面抗原。在接种疫苗期间引发这种反应可能会对 预防人类寄生虫病。