Regulation and function of B cells during malaria infection- Resubmission

疟疾感染期间 B 细胞的调节和功能 - Resubmission

• 批准号: 9188799
• 负责人: Jason S Stumhofer
• 金额: $ 51.13万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-04 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188799
• 关键词: Acute; Adolescence; Affinity; Age; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Antibody-mediated protection; Antigens; Antimalarials; B-Lymphocytes; BLR1 gene; Blood; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cessation of life; Child; Childhood; Culicidae; Data; Development; Disease; Drops; Egg White; Engineering; Generations; Goals; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Humoral Immunities; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Immunologic Memory; Infection; Knowledge; Lead; Link; Malaria; Malaria Vaccines; Mediating; Memory; Memory B-Lymphocyte; Monitor; Muramidase; Mus; Parasites; Pharmaceutical Preparations; Phenotype; Plasma Cells; Plasmodium; Population; Population Heterogeneity; Primary Infection; Process; Public Health; Receptors, Antigen, B-Cell; Regulation; Reporting; Resolution; Specificity; Spleen; Structure of germinal center of lymph node; Supporting Cell; T memory cell; T-Lymphocyte; Techniques; Testing; Time; Transgenic Organisms; Vaccines; base; design; global health; improved; innovation; insight; magnetic beads; malaria infection; man; memory CD4 T lymphocyte; mouse model; novel; public health relevance; response; secondary infection; tool; vaccine candidate; vaccine development

 DESCRIPTION (provided by applicant): The protozoan parasite Plasmodium is the causative agent of malaria, which remains one of the most prominent public health challenges in the world today. Plasmodium-specific antibody responses are important for protecting against subsequent reinfections in humans and mice. However, while mice are protected after a single infection, protective immunity is slow to develop in humans due to the requirement of repeated infections for the generation of protective antibodies. Our long-term goal is to determine how protective antibody responses are generated and maintained in mice after Plasmodium infection, so that we can utilize this information to understand why antibody-mediated immunity is slow to develop in humans. Plasmodium-specific memory B cells are generated after infection in mice and humans; however, surprisingly little information is available regarding their specificity, phenotype, origin and affinity for malarial antigens. Our preliminary studies indicate that there are layers of heterogeneity within the memory B cell pool after Plasmodium infection and we hypothesize that this heterogeneity in the memory B cell pool contributes to functional diversity in a secondary infection. We propose to (Aim 1) characterize heterogeneous populations of memory B cells after P. yoelii 17X infection in mice and determine their origin. We will then (Aim 2) determine the function of distinct subsets of memory B cells after secondary infection. Additionally, our preliminary studies have identified two populations of memory T cells that express markers associated with follicular helper T cells. We propose to (Aim 3) determine if these populations of memory T cells are capable of differentiating into functional follicular helpe T cells that can support Ab production in a secondary infection and whether they are required for protection after challenge. To accomplish these goals we have developed innovative tools to track parasite- specific B cell responses at the cellular level utilizing parasites engineered to express hen egg-white lysozyme (HEL). Using HEL-specific transgenic B cells and a novel magnetic-bead based enrichment technique we can monitor and track the fate of antigen-specific B cells after infection with HEL expressing parasites. These innovative tools and approaches will provide valuable insight into understanding how protective immunity against Plasmodium is generated, is maintained, and functions in a secondary immune response and will identify key components involved in this process.

 描述（由申请人提供）：原生动物寄生虫疟原虫是疟疾的病原体，疟疾仍然是当今世界最突出的公共卫生挑战之一。疟原虫特异性抗体应答对于保护人类和小鼠免受随后的再感染是重要的。然而，虽然小鼠在单次感染后受到保护，但由于需要重复感染以产生保护性抗体，因此保护性免疫在人类中发展缓慢。我们的长期目标是确定疟原虫感染后小鼠中保护性抗体反应是如何产生和维持的，以便我们可以利用这些信息来理解为什么抗体介导的免疫在人类中发展缓慢。疟原虫特异性记忆B细胞在感染小鼠和人类后产生;然而，令人惊讶的是，关于它们的特异性、表型、起源和对疟疾抗原的亲和力的信息很少。我们的初步研究表明，有层的异质性内的记忆B细胞池疟原虫感染后，我们假设，这种异质性的记忆B细胞池有助于功能多样性的二次感染。我们提出（目的1）表征约氏疟原虫17 X感染小鼠后记忆B细胞的异质群体并确定其来源。然后我们将（目的2）确定记忆B细胞的不同亚群在二次感染后的功能。此外，我们的初步研究已经确定了两个群体的记忆T细胞，表达标记物与滤泡辅助T细胞。我们建议（目的3）确定这些记忆T细胞群是否能够分化为功能性滤泡辅助T细胞，这些细胞可以支持继发感染中的Ab产生，以及它们是否需要在攻击后提供保护。为了实现这些目标，我们已经开发了创新的工具，以利用被工程化以表达鸡蛋白溶菌酶（HEL）的寄生虫在细胞水平上追踪寄生虫特异性B细胞应答。使用HEL特异性转基因B细胞和一种新的基于磁珠的富集技术，我们可以监测和跟踪抗原特异性B细胞在感染表达HEL的寄生虫后的命运。这些创新的工具和方法将提供有价值的见解，以了解如何产生，维持对疟原虫的保护性免疫，并在二次免疫反应中发挥作用，并将确定参与这一过程的关键组成部分。