Mechanisms and consequences of extrafollicular B cell activation during malaria

疟疾期间滤泡外 B 细胞激活的机制和后果

• 批准号: 10494205
• 负责人: Noah Sullivan Butler
• 金额: $ 64.71万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494205
• 关键词: Address; Affect; Affinity; Amino Acid Transporter; Amino Acids; Antigens; Antimalarials; B-Cell Activation; B-Lymphocytes; Biochemical; Blood; COVID-19; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Communicable Diseases; Data; Dengue; Detection; Development; Diet; Disease; Ebola; Epigenetic Process; Event; Failure; Genetic; Genetic Transcription; Glutamine; Goals; Human; Humoral Immunities; Hyperactivity; Hypoxia; Immune; Immune response; Immunity; Immunologic Memory; Immunology; Impairment; Individual; Infection; Infectious Disease Immunology; Interferons; Intervention; Knowledge; Link; Longevity; Longitudinal Studies; Malaria; Mediating; Memory B-Lymphocyte; Metabolic; Metabolism; Molecular; Mus; Nature; Nutrient; Parasites; Pathway interactions; Patients; Pattern recognition receptor; Plasma Cells; Plasmablast; Plasmodium; Population; Protozoan Infections; Reagent; Receptor Signaling; Reporting; Resistance; Resolution; Shapes; Signal Transduction; Spleen; Structure of germinal center of lymph node; Supplementation; System; Testing; Trypanosomiasis; base; imprint; improved; innovation; novel; novel strategies; nutrient deprivation; pathogen; plasma cell development; programs; response; single cell technology; tool; vaccinology

ABSTRACT There is currently a lack of mechanistic understanding of why humoral immunity against malaria is not efficiently induced and why Plasmodium infections are associated immune failures, even following repeated infections. Our long-term goal is to determine how Plasmodium parasites, and potentially other protozoan infections, co-opt and subvert humoral immunity, which will help with the identification and development of new immune-based interventions against devastating diseases like malaria. The objectives of this project are to define mechanisms that trigger initial humoral immune dysregulation and study the consequences of these events on the formation of durable humoral immune memory. Our central hypothesis is that robust humoral immunity does not develop efficiently because polyclonal B cell activation events establish a nutrient sink that impairs the metabolic, transcriptional and epigenetic programming and function of Plasmodium-specific memory B cells. The rationale for this project is linked to our recent discovery that Plasmodium infection results in a massive polyclonal expansion of B cells that function as a nutrient sink that limits protective memory B cell responses. Deletion of these B cells accelerates blood-stage Plasmodium parasite clearance and enhances humoral immune memory. Supplementing the diet of infected mice with a single amino acid is sufficient to overcome the nutrient sink and metabolic constraints imposed by these B cells and results in enhanced humoral immune memory responses. Despite our new findings, the molecular mechanisms governing the activation and function of immunoinhibitory B cells and the impact of these cells on the affinity and longevity of memory B cells remain critical knowledge gaps in our quest to improve humoral immunity against malaria. Two Aims address these priority questions. In the first Aim we will determine the molecular and cellular mechanisms that govern the expansion of these immunosuppressive B cells and investigate whether these populations are relevant to other infections associated with dysregulated humoral immunity. In the second Aim we will investigate the molecular and cellular consequences of immunosuppressive B cell expansions on the genetic and epigenetic programming of memory B cells. We have developed several innovative new reagents that afford unprecedented resolution for the study anti-malarial humoral immunity. The significance of this project is directly linked to our new findings showing that pathophysiological changes that occur during Plasmodium infection durably imprints on B cell fate and function. Thus, determining how these pathways coordinately regulate polyclonal B cell activation, development and humoral immunity will be broadly important to those studying infectious disease immunology and vaccinology.

抽象的 目前缺乏机械理解，为什么对疟疾的体液免疫力不高 引起的以及为什么疟原虫感染是相关的免疫衰竭，即使在反复感染之后也是如此。我们的 长期目标是确定疟原虫寄生虫以及其他潜在的原生动物感染，同上和 颠覆体液免疫，这将有助于识别和开发新的基于免疫的免疫力 诸如疟疾等毁灭性疾病的干预措施。该项目的目标是定义机制 这会触发最初的体液免疫失调并研究这些事件对形成的后果 耐用的体液免疫记忆。我们的中心假设是强大的体液免疫力不会发展 高效，因为多克隆B细胞激活事件建立了营养水槽，损害了代谢， 转录和表观遗传编程以及疟原虫特异性记忆B细胞的功能。理由 对于这个项目，我们最近发现疟原虫感染会导致巨大的多克隆 B细胞的扩展充当营养水槽，限制了保护性记忆B细胞反应。删除 这些B细胞加速了血液阶段寄生虫清除率并增强体液免疫 记忆。用单个氨基酸补充感染小鼠的饮食足以克服养分 这些B细胞施加的下沉和代谢约束，并导致体液上的免疫记忆增强 回答。尽管有新发现，但分子机制管理的激活和功能 免疫抑制性B细胞以及这些细胞对记忆B细胞的亲和力和寿命的影响 批判性知识差距在我们寻求改善疟疾的体液免疫力方面。两个目的解决这些 优先问题。在第一个目的中，我们将确定控制的分子和细胞机制 这些免疫抑制性B细胞的扩展并研究了这些人群是否与其他人相关 与失调的体液免疫相关的感染。在第二个目标中，我们将研究分子 免疫抑制B细胞扩展对遗传和表观遗传编程的细胞后果 记忆B单元。我们已经开发了一些创新的新试剂，这些试剂提供了前所未有的分辨率 为了研究抗疟疾的体液免疫。该项目的意义直接与我们的新发现有关 表明在疟原虫感染期间发生的病理生理变化在B细胞命运上持久烙印 和功能。因此，确定这些途径如何协同调节多克隆B细胞激活， 对于研究传染病免疫学的人来说，发育和体液免疫将至关重要 和疫苗学。