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The Development and Function of Plasmodium-specific memory B cells

疟原虫特异性记忆 B 细胞的发育和功能

基本信息

批准号：
10062845
负责人：
MARION PEPPER
金额：
$ 59.66万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-16 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062845
关键词：
Address Affect Affinity Antibodies Antibody Formation Antibody-Producing Cells Antigen Presentation Antigens Autoimmune Diseases B-Cell Antigen Receptor B-Lymphocyte Subsets B-Lymphocytes B-cell receptor repertoire sequencing Blood Cell Communication Cell physiology Cells Communicable Diseases Cytokine Signaling Development Disease Flow Cytometry Frequencies Generations Goals Gold Human Humoral Immunities Immune Immune Sera Immunization Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin-Secreting Cells Immunologics Infection Kinetics Knowledge Lead Ligands Maintenance Malaria Malaria Vaccines Mediating Memory Memory B-Lymphocyte Merozoite Surface Protein 1 Methods Modeling Molecular Mus Parasite Control Parasitemia Parasites Perception Phenotype Plasma Cells Plasmablast Plasmodium Plasmodium chabaudi Play Population Population Heterogeneity Proteins Reaction Receptor Activation Research Role Signal Transduction Source Structure of germinal center of lymph node T-Lymphocyte Tertiary Protein Structure Testing Time Vaccination Vaccines Work base cytokine first responder global health immunoregulation innovation magnetic beads malaria infection mouse model nanoparticle neutralizing antibody novel pathogen receptor receptor expression response secondary infection tool vaccine development

项目摘要

Memory B cells and long-lived plasma cells are responsible for producing neutralizing antibodies that can effectively eliminate a pathogen. Understanding the function of these cells in response to infection and how they can be induced and maintained by vaccination is therefore critical to eradicating diseases that are global health burdens. Malaria, caused by Plasmodium spp, is a major global health burden that is in urgent need of a vaccine. Over fifty years ago it was shown that transfer of human immune serum can neutralize Plasmodium parasites during the blood stage of infection. Little is known however about the Plasmodium-specific B cells that produce these antibodies due to the difficulties of studying low frequency antigen-specific B cells. Additionally, it is not understood how recently described populations of heterogeneous memory B cell (MBC) subsets induced by protein immunization form or function in response to infection. To clarify functional roles for distinct MBC subsets during malaria infection, tetramers were generated that identify Plasmodium-specific MBCs in both humans and mice. Multiparameter flow cytometry and single-cell B cell receptor sequencing revealed that long- lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated, classically defined IgG+ (IgG+), a previously unrecognized population of somatically hypermutated IgM+ (IgMhighIgDlow) MBCs and an unmutated IgD+ (IgMlowIgDhigh) MBC population. Surprisingly, Plasmodium-specific IgM+ antibody dominated the early response to a secondary infection. Further analyses revealed that upon rechallenge, IgM+ MBCs rapidly form two antibody-secreting populations: T cell-independent plasma cells and T-dependent IgM+ and IgG+ plasmablasts. IgM+ MBCs are therefore rapid, plastic, first responders to Plasmodium rechallenge and should be targeted by vaccine strategies. We are now poised to further characterize these and other Plasmodium-specific B cell populations to determine their unique contributions to protection against malaria in both humans and relevant murine models. The central hypothesis of this application is that the development of functionally heterogeneous yet synergistic populations of memory B cells will be required for vaccine-mediated protection to Plasmodium. The goals of this proposal are to identify the molecular and cellular mechanisms that lead to the formation of these distinct MBC subsets and to determine how these cells contribute to protection against malaria in mice and humans. This innovative approach could provide the information required to develop the first effective vaccine against malaria.

记忆B细胞和长寿浆细胞负责产生中和

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antigen- and scaffold-specific antibody responses to protein nanoparticle immunogens.

DOI：
10.1016/j.xcrm.2022.100780
发表时间：
2022-10-18
期刊：
CELL REPORTS MEDICINE
影响因子：
14.3
作者：
Kraft, John C.;Pham, Minh N.;Shehata, Laila;Brinkkemper, Mitch;Boyoglu-Barnum, Seyhan;Sprouse, Kaitlin R.;Walls, Alexandra C.;Cheng, Suna;Murphy, Mike;Pettie, Deleah;Ahlrichs, Maggie;Sydeman, Claire;Johnson, Max;Blackstone, Alyssa;Ellis, Daniel;Ravichandran, Rashmi;Fiala, Brooke;Wrenn, Samuel;Miranda, Marcos;Sliepen, Kwinten;Brouwer, Philip J. M.;Antanasijevic, Aleksandar;Veesler, David;Ward, Andrew B.;Kanekiyo, Masaru;Pepper, Marion;Sanders, Rogier W.;King, Neil P.
通讯作者：
King, Neil P.

Plasmodium infection disrupts the T follicular helper cell response to heterologous immunization.