Regulation of humoral immunity in a mouse model of hookworm infection

钩虫感染小鼠模型体液免疫的调节

• 批准号: 500725705
• 负责人: Professor Dr. David Vöhringer
• 金额: --
• 依托单位: Infektionsbiologische Abteilung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/500725705?language=en
• 关键词: Regulation; humoral; immunity; mouse; model

Estimated 700 million people are affected by hookworm infections world-wide leading to major socioeconomic problems and a pronounced health impact caused by anemia, malnutrition and growth retardation of children. While medications can reduce worm burden they are often of low efficiency due to reinfections and may lead to the emergence of drug resistance. Vaccines are not yet available for human hookworm infections. The helminth Nippostrongylus brasiliensis (Nb) is a frequently used laboratory model to study the mechanisms of hookworm infections including pathways of protective immunity in mice. Nb infections elicit a strong type 2 immune response in the lung and small intestine with pronounced eosinophilia, high IgE levels and accumulation of Th2 cells and ILC2s. The focus of this proposal is the analysis of the humoral immune response to Nb especially after secondary infection or immunization with a single Nb-derived protein. We could previously show that during Nb infection the IL-4/IL-13-induced transcription factor STAT6 is required in B cells for germinal center (GC) formation in addition to its known function for class switch recombination to IgE. We further identified STAT6-regulated genes in B cells that we will now functionally characterize as part of this proposal to uncover how these genes may be involved in the GC response, plasma cell (PC) differentiation and formation of memory B cells. Using a fate-mapping approach, we will determine the differentiation and persistence of memory B cells and PCs after primary and secondary Nb infection. We will also analyze the B cell receptor (BCR) repertoire of fate-mapped cells and determine the linked BCR/transcriptome profile in single cells to identify expanded clones from which BCRs can be cloned and used to identify Nb-derived antigens or generate BCR-transgenic mice. Recently, we identified a new Nb-derived antigen that provides protective immunity against a Nb challenge infection. The protective effect occurs in the skin and is lost in basophil-deficient mice suggesting that it requires antibody-mediated activation of basophils. Further characterization of the humoral immune response to this antigen could lead to development of new vaccination strategies against helminths in the future.

据估计，全世界有7亿人受到钩虫感染的影响，导致重大的社会经济问题，并因贫血、营养不良和儿童发育迟缓而对健康造成明显影响。虽然药物可以减少蠕虫的负担，但由于再感染，它们通常效率低下，并可能导致耐药性的出现。目前还没有针对人类钩虫感染的疫苗。巴西日本圆线虫（Nippostrongylus brasiliensis，Nb）是研究钩虫感染机制（包括小鼠保护性免疫途径）的常用实验室模型。Nb感染在肺和小肠中引起强烈的2型免疫应答，具有显著的嗜酸性粒细胞增多、高IgE水平和Th 2细胞和ILC 2的积累。该提案的重点是分析对Nb的体液免疫应答，特别是在二次感染或用单一Nb衍生蛋白免疫后。我们以前可以表明，在Nb感染过程中，IL-4/IL-13诱导的转录因子STAT 6是B细胞中形成生发中心（GC）所必需的，除了其已知的类别转换重组为IgE的功能之外。我们进一步鉴定了B细胞中的STAT 6调控基因，我们现在将其功能表征作为本提案的一部分，以揭示这些基因如何参与GC反应、浆细胞（PC）分化和记忆B细胞的形成。使用命运映射方法，我们将确定记忆B细胞和PC在原发性和继发性Nb感染后的分化和持久性。我们还将分析命运映射细胞的B细胞受体（BCR）库，并确定单细胞中相关的BCR/转录组谱，以鉴定可从中克隆BCR并用于鉴定Nb衍生抗原或产生BCR的扩增克隆。转基因小鼠。最近，我们鉴定了一种新的Nb衍生抗原，其提供针对Nb攻击感染的保护性免疫。保护作用发生在皮肤中，在嗜碱性粒细胞缺陷小鼠中丧失，表明它需要抗体介导的嗜碱性粒细胞活化。对这种抗原的体液免疫应答的进一步表征可能会导致未来针对蠕虫的新疫苗接种策略的开发。