Development and function of humoral immunity in the Jamaican fruit bat, Artibeus jamaicensis

牙买加果蝠 Artibeus jamaicensis 体液免疫的发育和功能

• 批准号: 10452311
• 负责人: Hannah Kim Frank
• 金额: $ 27.9万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-18 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452311
• 关键词: Adaptive Immune System; Address; Affinity; Aliquot; Animals; Antibodies; Antibody Repertoire; Antibody Response; Antibody titer measurement; Antigens; Avidity; B-Cell Antigen Receptor; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Blood specimen; Body Size; Cell Culture Techniques; Cells; Cellular Immunity; Central America; Chiroptera; Clonal Expansion; Clone Cells; Communicable Diseases; Comparative Genomic Analysis; DNA; Data; Deletion Mutation; Development; Disease; Exposure to; Fever; Frequencies; Fruit; Future; Gene Combinations; Gene Rearrangement; Genes; Genetic; Genetic Recombination; Genomic DNA; Genomics; Health; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; Immunologic Memory; Immunologics; Individual; Infection; Insertion Mutation; Intervention; Investigation; Jamaican; Knowledge; Lead; Malignant Neoplasms; Marburgvirus; Measures; Mediating; Memory; Memory B-Lymphocyte; Monitor; Mutate; Mutation; Natural Immunity; Neutralization Tests; Organ; Organism; Population; Prevention; Public Health; Rabies; Rabies virus; Reagent; Research; Research Personnel; Role; SARS coronavirus; Serology; Somatic Mutation; South America; T-Lymphocyte; Techniques; Testing; Time; Vaccinated; Vaccination; Vaccines; Viral; Virus; Virus Diseases; Zoonoses; adaptive immunity; bat-borne; cell mediated immune response; cell type; cohort; experience; experimental study; immunoglobulin receptor; improved; insight; next generation; pathogen; peripheral blood; prevent; receptor; response; transcriptome; transcriptomics

Project Summary Bats host many viruses, seemingly without disease, that cause lethal infections in humans and other non-bat species, including rabies, Marburg fever virus and SARS-related coronaviruses. A greater understanding of the bat immune system – how it responds to viruses, how it differs from the human immune system – could lead to improved approaches for treating or even avoiding infection in humans. The immune response consists of two major branches: the nonspecific innate response and the pathogen-specific adaptive response. Although numerous studies have investigated innate immunity in bats, very little is known about their adaptive immune system. The long-term objective of the proposed research is to enhance understanding of adaptive immunity in bats. A key feature of adaptive immunity is humoral immunity; this immune response is mediated by antibodies, also known as immunoglobulins. The hyper-diverse immunoglobulin repertoire is generated through a combination of gene recombination, DNA insertions and deletions, and somatic mutation of the antibody sequence. While immunoglobulins have been detected in several serological studies of bats, the true extent of the diversity of bat immunoglobulin repertoires, the degree to which bats rely on gene rearrangement vs. somatic mutation to generate these repertoires, how mutation of the immunoglobulins correlates with neutralization of pathogens, or the B cell subsets that arise in response to infection remain unknown. The proposed study will use rabies virus vaccination followed by rabies virus infection in Jamaican fruit bats to generate the most comprehensive understanding of B cell-mediated adaptive immunity in bats to date. Jamaican fruit bats are common across Central and South America, where rabies remains a serious threat, and are naturally infected by rabies virus. This research will use long-read sequencing to characterize the germline genes that provide the starting diversity for the immunoglobulin repertoire. Next generation genomic techniques will be used to track the development of rearranged immunoglobulin repertoires, monitor expansion of specific B cell clones, and quantify the degree of somatic mutation in antigen-exposed antibodies across vaccination and challenge with rabies. Single-cell transcriptomics will be used to characterize the B cell subsets that arise in response to immune challenges, and binding assays and rabies neutralization tests will facilitate an understanding of how antibody maturation correlates with function. Comparison of the immune responses of bats to vaccination and infection will be used to investigate immunity in controlled and natural contexts. This research will provide important information on the adaptive immune system of bats that is currently lacking. These data will provide insight into the differences in immune responses between bats and humans to a shared pathogen and can be used to develop new rabies prevention or intervention approaches. The framework and immunological data generated by this project will also allow for specific investigations of B-cell mediated immunity to any infection.

项目概要 蝙蝠体内有许多看似没有疾病的病毒，可对人类和其他非蝙蝠动物造成致命感染。 物种，包括狂犬病、马尔堡热病毒和 SARS 相关冠状病毒。 蝙蝠免疫系统——它如何对病毒做出反应，它与人类免疫系统有何不同——可能会导致 治疗甚至避免人类感染的改进方法免疫反应包括两种。 主要分支：非特异性先天反应和病原体特异性适应性反应。 大量研究调查了蝙蝠的先天免疫，但人们对它们的适应性免疫系统知之甚少 拟议研究的长期目标是增强对适应性免疫的理解。 蝙蝠的适应性免疫的一个关键特征是体液免疫；这种免疫反应是由抗体介导的。 也称为免疫球蛋白，高度多样化的免疫球蛋白库是通过 基因重组、DNA插入和缺失以及抗体体细胞突变的组合 虽然在几项蝙蝠血清学研究中已经检测到了免疫球蛋白，但其真实程度仍然存在。 蝙蝠免疫球蛋白库的多样性，蝙蝠依赖基因重排与体细胞的程度 突变产生这些库，免疫球蛋白的突变如何与中和相关 病原体或响应感染而产生的 B 细胞亚群仍然未知。 使用狂犬病病毒疫苗接种，然后在牙买加果蝠中感染狂犬病病毒，以产生最大的 迄今为止，对牙买加果蝠 B 细胞介导的适应性免疫的全面了解。 在中美洲和南美洲很常见，狂犬病仍然是一个严重的威胁，并且是自然感染的 这项研究将使用长读长测序来表征提供狂犬病病毒的种系基因。 下一代基因组技术将用于追踪免疫球蛋白库的多样性。 重排免疫球蛋白库的发展，监测特定 B 细胞克隆的扩增，以及 量化疫苗接种和攻击过程中抗原暴露抗体的体细胞突变程度 单细胞转录组学将用于表征免疫反应中产生的 B 细胞亚群。 挑战、结合测定和狂犬病中和测试将有助于了解抗体如何 蝙蝠对疫苗接种和感染的免疫反应的比较与成熟相关。 这项研究将用于研究受控和自然环境中的免疫力。 目前缺乏有关蝙蝠适应性免疫系统的信息，这些数据将提供深入了解。 蝙蝠和人类对共同病原体的免疫反应存在差异，可用于 制定新的狂犬病预防或干预方法 生成的框架和免疫学数据。 该项目还将允许对 B 细胞介导的针对任何感染的免疫进行具体研究。