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 目前对于为什么针对疟疾的体液免疫不能有效地缺乏机制理解 以及为什么疟原虫感染与免疫失败相关，即使是在重复感染后也是如此。我们的 长期目标是确定疟原虫寄生虫以及潜在的其他原生动物感染如何共同选择和传播 颠覆体液免疫，这将有助于识别和开发新的基于免疫的 针对疟疾等毁灭性疾病的干预措施。该项目的目标是定义机制 引发最初的体液免疫失调并研究这些事件对形成的影响 持久的体液免疫记忆。我们的中心假设是，强大的体液免疫不会发展 有效地，因为多克隆 B 细胞激活事件建立了一个损害代谢的营养库， 疟原虫特异性记忆 B 细胞的转录和表观遗传编程和功能。理由 这个项目与我们最近的发现有关，即疟原虫感染会导致大量的多克隆 B 细胞的扩张充当营养库，限制保护性记忆 B 细胞的反应。删除 这些 B 细胞可加速血液阶段疟原虫寄生虫的清除并增强体液免疫 记忆。在受感染小鼠的饮食中补充单一氨基酸就足以克服营养不良 这些 B 细胞施加的库和代谢限制，导致体液免疫记忆增强 回应。尽管我们有新的发现，但控制激活和功能的分子机制 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仍然存在 我们在寻求提高针对疟疾的体液免疫力方面存在关键的知识差距。有两个目标解决这些问题 优先问题。在第一个目标中，我们将确定控制细胞的分子和细胞机制。 扩增这些免疫抑制性 B 细胞，并研究这些细胞群是否与其他细胞相关 与体液免疫失调相关的感染。在第二个目标中，我们将研究分子 免疫抑制 B 细胞扩增对遗传和表观遗传编程的细胞影响 记忆B细胞。我们开发了多种创新试剂，可提供前所未有的分辨率 用于研究抗疟疾体液免疫。该项目的重要性与我们的新发现直接相关 表明疟原虫感染期间发生的病理生理变化持久地影响 B 细胞的命运 和功能。因此，确定这些途径如何协调调节多克隆 B 细胞激活， 发育和体液免疫对于研究传染病免疫学的人来说非常重要 和疫苗学。