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

B-1细胞介导的伯氏柯克斯体感染免疫机制

• 批准号: 10155409
• 负责人: Guoquan Zhang
• 金额: $ 21.34万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155409
• 关键词: Acute; Aerosols; American soldier; Anti-Inflammatory Agents; Antibodies; Australia; B-Lymphocytes; Biological Warfare; Categories; Cells; Cellular Immunity; Chronic; Chronic Disease; Coxiella burnetii; Dangerousness; Development; Diagnosis; Disease; Disease Outbreaks; Environmental Risk Factor; Erythema; Exposure to; Formalin; Goals; Gram-Negative Bacteria; Headache; Health; Home; Host Defense; Human; Hypersensitivity skin testing; Immune response; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Inflammatory Response; Knowledge; Lead; Life Style; Mediating; Middle East; Monitor; Mus; Nature; Netherlands; Organism; Outcome; Phagocytes; Phase; Play; Prevention; Prevention strategy; Production; Public Health; Q Fever; Reporting; Research; Resistance; Role; Serology; Soldier; Spleen; Splenomegaly; Swelling; Symptoms; T-Lymphocyte; Testing; Therapeutic; Ultraviolet Rays; Vaccinated; Vaccination; Vaccines; Whole Cell Vaccine; Work; Zoonoses; aerosolized; biosecurity; bioterrorism/chemical warfare; cytokine; flu; high risk; immunoprophylaxis; innovation; mouse model; novel; novel strategies; pathogen; pathogenic bacteria; prophylactic; seropositive; side effect; skin vaccination; weapons

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.

摘要 Q热是一种世界性的人畜共患病，由专性细胞内革兰氏阴性菌引起， 贝氏柯克斯体人类Q热可发展成为一种严重的慢性、可能致命的疾病。虽然这 生物体以前武器化，目前被列为B类选择剂，没有疫苗是 在美国可商购获得用于预防人Q热。因此，发展安全和 有效的预防和治疗策略，以控制C。贝氏体感染仍然是一个重要的目标 公共卫生和国家生物安全。然而，在有关这一问题的知识方面存在着根本性的差距。 宿主对C.贝氏自然感染。为了填补这一空白，新的R21应用程序 目的探讨B1 B细胞是否在控制细菌复制和调节宿主中起关键作用 C.布氏气溶胶感染尽管C.贝氏菌是一种细胞内细菌 病原体，我们的初步研究表明，C.贝氏体感染引起更严重的脾肿大 B1细胞缺陷小鼠脾脏中的细菌负荷更高，表明B1细胞在体内发挥重要作用。 在宿主防御中的作用。贝氏体感染这个应用程序的目的是使用C。贝氏 气溶胶感染小鼠模型，以确定B1细胞介导的保护性免疫机制， C.贝氏自然感染。为了实现这一目标，提出了两个具体目标，以测试中央 假设B1细胞介导抗C.贝氏体的感染取决于其能力， 控制细菌复制和调节炎症反应。目的1将确定B1细胞是否可以介导 C.死亡伯内特氏菌我们将确定i）B1细胞是否在宿主防御C.贝氏 气溶胶感染;和ii）B1细胞可以作为吞噬细胞介导C.伯内特氏菌目标2将 确定B1细胞是否可以调节C.贝氏体感染诱导的炎症反应。我们将确定i） B1细胞是否是调节雾化C. burnetii诱导的炎症反应;以及ii）如何 B1细胞调节C.贝氏体感染作为拟议研究的一项成果， 我们希望能加深我们对B1细胞介导的保护性免疫机制的理解， C.贝氏自然感染。这将对人类健康产生重大积极影响，因为它将提供 开发新的免疫策略对抗Q热的关键信息。