Mechanisms of B-1 Cell-Mediated Immunity Against Coxiella burnetii Infection

摘要 Q热是一种由专性细胞内革兰氏阴性细菌引起的世界性人畜共患疾病， 伯氏柯克斯体。人类Q热可能发展成一种严重的慢性疾病，可能是致命的。虽然这件事 以前被武器化并目前被归类为B类选择剂的生物体，没有疫苗 在美国可用于预防人类Q热的商业用途。因此，安全和安全的发展 控制伯氏梭菌感染的有效预防和治疗策略仍然是一个重要目标 公共卫生和国家生物安全。然而，关于这一问题的认识存在着根本的差距 伯氏梭菌自然感染宿主免疫应答机制的研究。为了填补这一空白，这个新的R21应用程序 旨在探讨B1B细胞是否在控制细菌复制和调节宿主方面发挥关键作用 布氏弧菌气溶胶感染过程中的免疫反应。尽管伯氏梭菌是一种胞内细菌 病原体，我们的初步研究表明，感染伯氏梭菌会导致更严重的脾肿大。 以及B1细胞缺陷小鼠脾中较高的细菌负荷，表明B1细胞在 在宿主抵抗伯氏梭菌原发感染中的作用。这个应用程序的目的是使用一种伯氏梭菌 气溶胶感染小鼠模型探讨B1细胞介导的保护性免疫机制 伯氏梭菌自然感染。为了实现这一目标，提出了两个具体目标来测试中央 假设B1细胞介导的对伯氏弧菌感染的保护性免疫依赖于其能力 控制细菌复制，调节炎症反应。目标1将确定B1细胞是否能够调节 杀死伯内提毛虫。我们将确定i)B1细胞是否在宿主防御伯氏柯萨奇杆菌中发挥关键作用 气溶胶感染；以及ii)B1细胞可以作为吞噬细胞来调节伯氏梭菌的清除。目标2将 确定B1细胞是否能调节伯氏梭菌感染引起的炎症反应。我们将确定i) B1细胞是否对调节伯氏梭菌气雾化诱导的炎症反应至关重要；以及ii)如何 在伯氏梭菌感染过程中，B1细胞调节炎症反应。作为拟议研究的结果， 我们希望加深我们对B1细胞介导的保护性免疫机制的理解。 伯氏梭菌自然感染。这将对人类健康产生重大的积极影响，因为它将提供 开发针对Q热的新免疫治疗策略的关键信息。

Abstract Q fever is a worldwide zoonotic disease that is caused by the obligate intracellular Gram-negative bacterium, Coxiella burnetii. Human Q fever can develop into a severe chronic, potentially fatal disease. Although this organism previously weaponized and currently classified as a category B select agent, no vaccine is commercially available for the prevention of human Q fever in the US. Therefore, the development of safe and effective prophylactic and therapeutic strategies for controlling C. burnetii infection remains an important goal for public health and national biosecurity. However, there is a fundamental gap in the knowledge regarding the mechanisms of host immune response to C. burnetii natural infection. To fill this gap, this new R21 application aims to explore whether B1 B cells play a critical role in controlling bacterial replication and regulating host immune response during C. burentii aerosol infection. Despite C. burnetii being an intracellular bacterial pathogen, our preliminary study demonstrates that a C. burnetii infection induces more severe splenomegaly and higher bacterial burden in the spleens of B1 cell deficient mice, suggesting that B1 cells play an important role in host defense against primary C. burnetii infection. The objective of this application is to use a C. burnetii aerosol infection mouse model to determine the mechanisms of B1 cell-mediated protective immunity against C. burnetii natural infection. To achieve this objective, two specific aims were proposed to test the central hypothesis that B1 cell-mediated protective immunity against C. burnetii infection depends on its abilities to control bacterial replication and regulate inflammatory response. Aim 1 will determine if B1 cells can mediate killing of C. burnetii. We will determine whether i) B1 cells play a critical role in host defense against C. burnetii aerosol infection; and ii) B1 cells can function as phagocytes to mediate clearance of C. burnetii. Aim 2 will determine if B1 cells can regulate C. burnetii infection-induced inflammatory responses. We will determine i) whether B1 cells are crucial for regulating aerosolized C. burnetii-induced inflammatory response; and ii) how B1 cells regulate inflammatory response during C. burnetii infection. As an outcome of the proposed research, we expect to enhance our understanding of the mechanisms of B1 cell-mediated protective immunity against C. burnetii natural infection. This will have significant positive effects on human health, because it will provide critical information for developing novel immunotherapeutic strategies against Q fever.