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

项目摘要 蝙蝠携带许多病毒，似乎没有疾病，这些病毒会在人类和其他非蝙蝠身上造成致命的感染 这些物种包括狂犬病、马尔堡热病毒和与SARS相关的冠状病毒。更好地理解 蝙蝠的免疫系统--它如何应对病毒，它与人类的免疫系统有何不同--可能会导致 改进了治疗甚至避免人类感染的方法。免疫反应由两个部分组成 主要分支：非特异性先天反应和病原体特异性适应性反应。虽然 许多研究对蝙蝠的先天免疫进行了研究，但对它们的获得性免疫知之甚少。 系统。拟议研究的长期目标是加强对获得性免疫的了解 蝙蝠。获得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。超级多样化的免疫球蛋白谱系通过一种 基因重组、DNA插入和缺失以及抗体的体细胞突变的组合 序列。虽然在蝙蝠的几项血清学研究中检测到了免疫球蛋白，但真正的 蝙蝠免疫球蛋白谱系的多样性，蝙蝠对基因重排的依赖程度与体细胞 突变来产生这些谱系，免疫球蛋白的突变如何与 病原体或B细胞亚群对感染的反应仍不清楚。拟议的研究将 在牙买加果蝠中使用狂犬病病毒疫苗接种后再感染狂犬病病毒可以产生最多的 到目前为止，对蝙蝠B细胞介导的适应性免疫的全面了解。牙买加果蝠是 狂犬病在中美洲和南美洲很常见，在那里狂犬病仍然是一个严重的威胁，并自然感染 被狂犬病病毒感染。这项研究将使用长阅读测序来表征提供 开始多样化的免疫球蛋白曲目。下一代基因组技术将用于追踪 重排免疫球蛋白谱系的开发，监测特定B细胞克隆的扩张，以及 量化抗原暴露抗体在接种和挑战过程中的体细胞突变程度 狂犬病。单细胞转录学将被用来表征免疫反应中出现的B细胞亚群 挑战，结合化验和狂犬病中和试验将有助于理解抗体如何 成熟度与功能相关。蝙蝠对疫苗接种和感染免疫应答的比较 将被用来研究受控和自然情况下的免疫力。这项研究将提供重要的 目前缺乏关于蝙蝠适应性免疫系统的信息。这些数据将提供对 蝙蝠和人类对相同病原体的免疫反应的差异可以用来 开发新的狂犬病预防或干预方法。框架和产生的免疫学数据 该项目还将允许对B细胞介导的对任何感染的免疫进行具体研究。

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.