Unravelling the role of B cells in mediating the immune response and providing protection against Salmonella infection using gene-edited chickens

鸡是人类饮食中动物源性蛋白的主要来源之一。然而，他们经常接触到各种病原体，威胁到他们的福利，并给家禽业造成巨大的经济损失。此外，一些病原体，如沙门氏菌，可传播给人类，每年可导致大量人死亡。在2600个沙门氏菌血清型中，肠炎沙门氏菌(S.Enteritidis)是大多数国家与人类疾病有关的最常见的血清型。目前的疫苗接种战略远远不足以管理和控制家禽中的这种疾病。因此，开发基于免疫调节的有效疫苗接种策略来解决这一公共卫生问题越来越受到人们的关注。B淋巴细胞分泌针对每个入侵病原体的特异性抗体，这对于开发能够提供对各种疾病的保护的有效疫苗接种策略至关重要。B细胞在沙门氏菌防御机制中的作用是一个长期存在争议的问题。这归因于生产B细胞缺陷鸡的传统方法效率低下，以及它们的生理副作用。转基因动物一直是研究特定分子作用的极其有用的工具。这项建议的主要目的是利用转基因鸡来揭示B淋巴细胞在肠炎沙门氏菌发病机制中的作用。在第一个目标中，将利用缺乏抗体的B细胞敲除鸡来探讨B细胞在沙门氏菌发病机制中的作用，以及在目前用于控制家禽沙门氏菌的活疫苗的保护作用中所起的作用。这一目标将揭示B细胞对沙门氏菌感染做出反应的潜在机制，并控制异嗜性细胞的功能和转录活性，这对宿主防御沙门氏菌的机制至关重要。这将有助于开发免疫调节策略和更有效的疫苗来预防鸡只感染沙门氏菌。在第二个目的中，我将研究通过体内过继转移表达mCherry的鸡的脾和骨髓B细胞来恢复B细胞缺陷鸡的免疫反应的可能性。根据其来源识别B细胞的免疫学特性，将使精确调控其功能成为可能。最终，该项目将改善鸡和人类的健康和福利，并防止与这一公共卫生问题相关的巨大经济损失。

Chickens are one of the major sources of animal-derived protein in human diet. However, they are regularly exposed to various pathogens which threaten their welfare and cause huge economic losses to the poultry industries. Moreover, some pathogens, such as Salmonella, are transmittable to humans and can cause the death of lots of people every year. Out of 2,600 Salmonella serotypes, Salmonella Enteritidis (S. Enteritidis) is the most common serotype associated with human illness in most countries. Current vaccination strategies are far from being sufficient to manage and control this disease in poultry. Therefore, there is growing interest to develop immune modulation based effective vaccination strategies for this public health problem. B lymphocytes secrete antibodies specific for each invading pathogen and this is critical for the development of effective vaccination strategies capable of providing protection against various diseases. The role of B cells in the defense mechanism against Salmonella is a long-standing matter of debate. This is attributed to the traditional inefficient methods employed to produce B cells deficient chickens, and their physiological side effects. Genetically modified animals have always been extremely useful tools to study the role of specific molecules. The main objective of this proposal is to unravel the role of B lymphocytes in the pathogenesis of Salmonella Enteritidis using genetically modified chickens. In the first aim, B cells knockout chickens, deficient of antibodies, will be utilized to explore the role of B cells in the pathogenesis of Salmonella and in mediating the protective effects of live vaccine currently used to control Salmonella in poultry. This aim will uncover the underlying mechanism by which B cells respond to Salmonella infection and control the functional and transcriptomic activities of heterophils which are critical for the host defense mechanism against Salmonella. This will help to develop immune-modulation strategies and more effective vaccines against Salmonella infection in chickens. In the second aim, I will investigate the likelihood of restoring the immune response in B cells deficient chickens using in vivo adoptive transfer of splenic and bone marrow B cells from mCherry expressing chickens. Identifying the immunological characteristics of B cells based on their source will make it possible to modulate and control their functions precisely. Ultimately, this project will improve the health and welfare of chickens and humans, and prevent huge economic losses associated with this public health problem.