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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 Q热是一种世界范围内的人畜共患疾病，由专性细胞内革兰氏阴性菌引起，伯内氏柯克斯体。人类 Q 热可能发展成一种严重的慢性、可能致命的疾病。虽然这生物体之前被武器化，目前被归类为 B 类选择剂，没有疫苗在美国可用于预防人类 Q 热。因此，发展安全、控制伯氏念珠菌感染的有效预防和治疗策略仍然是一个重要目标为了公共卫生和国家生物安全。然而，人们对这方面的认识存在着根本性的差距。宿主对伯氏念珠菌自然感染的免疫反应机制。为了填补这一空白，这个新的 R21 应用程序旨在探索B1 B细胞是否在控制细菌复制和调节宿主方面发挥关键作用 C. burentii 气溶胶感染期间的免疫反应。尽管伯内特念珠菌是一种细胞内细菌病原体，我们的初步研究表明伯内特念珠菌感染会引起更严重的脾肿大 B1 细胞缺陷小鼠脾脏中的细菌负担较高，表明 B1 细胞在在宿主防御原发性伯氏念珠菌感染中的作用。本申请的目的是使用 C. burnetii 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. burnetii 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 细胞介导的针对伯氏念珠菌感染的保护性免疫取决于其以下能力：控制细菌复制并调节炎症反应。目标 1 将确定 B1 细胞是否可以介导杀死 C. burnetii。我们将确定 i) B1 细胞是否在宿主防御伯氏念珠菌中发挥关键作用气溶胶感染； ii) B1 细胞可以作为吞噬细胞发挥作用，介导伯氏念珠菌的清除。目标2将确定 B1 细胞是否可以调节伯内特念珠菌感染诱导的炎症反应。我们将确定 i) B1 细胞对于调节雾化伯纳特念珠菌诱导的炎症反应是否至关重要； ii) 如何 B1 细胞在伯内特念珠菌感染期间调节炎症反应。作为拟议研究的结果，我们希望加强对 B1 细胞介导的保护性免疫机制的理解 C. burnetii 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 热的新型免疫治疗策略的关键信息。