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质的主要来源之一。然而，它们经常暴露于各种病原体，这些病原体威胁着它们的健康，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，每年可导致许多人死亡。在2,600种沙门氏菌血清型中，肠道沙门氏菌（S。在大多数国家，肠杆菌（肠杆菌）是与人类疾病相关的最常见血清型。目前的疫苗接种策略远远不足以管理和控制家禽中的这种疾病。因此，人们越来越关注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。B淋巴细胞分泌对每种入侵病原体具有特异性的抗体，这对于开发能够提供针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。这是由于传统的生产B细胞缺陷鸡的方法效率低下，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非常有用的工具。本提案的主要目的是利用转基因鸡阐明B淋巴细胞在沙门氏菌肠炎发病机制中的作用。 在第一个目标中，B细胞敲除鸡，缺乏抗体，将被用于探索B细胞在沙门氏菌的发病机制中的作用，并介导目前用于控制家禽沙门氏菌的活疫苗的保护作用。这一目标将揭示潜在的机制，其中B细胞响应沙门氏菌感染和控制的功能和转录组活性的嗜异性细胞，这是至关重要的宿主防御机制，对沙门氏菌。这将有助于开发免疫调节策略和更有效的疫苗来预防鸡沙门氏菌感染。在第二个目标中，我将研究使用来自mCherry表达鸡的脾和骨髓B细胞的体内过继转移来恢复B细胞缺陷鸡的免疫应答的可能性。根据B细胞的来源确定其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.