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: 10376468
• 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/10376468
• 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.

摘要 目前缺乏对为什么抗疟疾的体液免疫不有效的机制性理解 以及为什么疟原虫感染与免疫失败有关，即使是在重复感染之后。我们 长期目标是确定疟原虫寄生虫和潜在的其他原生动物感染是如何协同和 颠覆体液免疫，这将有助于识别和开发新的免疫基础 针对疟疾等毁灭性疾病的干预措施。该项目的目标是确定机制， 引发初始体液免疫失调，并研究这些事件对形成 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 因为多克隆B细胞活化事件建立了损害代谢的营养库， 疟原虫特异性记忆B细胞的转录和表观遗传编程和功能。的理由 这个项目与我们最近发现的疟原虫感染导致大规模的多克隆 作为限制保护性记忆B细胞反应的营养库的B细胞的扩增。删除 这些B细胞加速血液阶段疟原虫的清除，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素 这些B细胞施加的下沉和代谢限制，并导致增强的体液免疫记忆 应答尽管我们有了新的发现，但控制细胞激活和功能的分子机制仍然是未知的。 免疫抑制性B细胞和这些细胞对记忆B细胞的亲和力和寿命的影响仍然存在 在我们寻求提高疟疾体液免疫力方面存在重大知识差距。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增殖的分子和细胞机制。 扩增这些免疫抑制B细胞，并研究这些群体是否与其他免疫抑制相关。 与体液免疫失调有关的感染。在第二个目标中，我们将研究分子 免疫抑制性B细胞扩增对遗传和表观遗传编程的细胞后果 记忆B细胞。我们已经开发了几种创新的新试剂，提供前所未有的分辨率 用于抗疟疾体液免疫的研究。这个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细胞活化， 发展和体液免疫将是广泛重要的那些研究传染病免疫学 疫苗学