The Role of Antibody-Mediated Protective Immunity Against Q fever

抗体介导的 Q 热保护性免疫的作用

• 批准号: 7876866
• 负责人: Guoquan Zhang
• 金额: $ 18.01万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876866
• 关键词: Acute; Aerosols; Animals; Antibodies; Antibody-mediated protection; Antigen Targeting; Antigens; Binding; Bioterrorism; Breathing; Categories; Cellular Immunity; Chronic; Chronic Disease; Complement; Coxiella burnetii; Cytolysis; Development; Disease; Fc Receptor; Goals; Gram-Negative Bacteria; Health; Host Defense; Human; Immune response; Immunity; Immunoglobulin G; Immunoglobulins; Immunology; Immunotherapeutic agent; Infection; Interferons; Knowledge; Laboratories; Lead; Licensing; Lipopolysaccharides; Lung; Mediating; Missouri; Mus; Nature; O Antigens; Outcomes Research; Pathogenesis; Phagocytosis; Phase; Play; Pneumonia; Population; Proteins; Public Health; Q Fever; Qualifying; Role; Route; T-Lymphocyte; Testing; Universities; Vaccinated; Vaccine Design; Vaccines; Virulent; Work; aerosolized; atypical pneumonia; base; biosecurity; cell type; experience; extracellular; innovation; killings; macrophage; mouse model; novel strategies; pathogen; prevent; programs; public health relevance; transmission process; vaccine candidate

DESCRIPTION (provided by applicant): Coxiella burnetii is an obligate intracellular gram-negative bacterium that causes the worldwide zoonotic disease, Q fever. Natural human infections commonly occur via inhalation of infectious aerosols, manifest clinically as atypical pneumonia, and can develop into a severe, fatal chronic disease. C. burnetii is an understudied category B select agent, and there is no licensed vaccine in the US. Creation of a safe and effective vaccine for preventing human Q fever is an important public health and national biosecurity goal. The long-term goal of this program is to develop new approaches to discovery of safe, effective vaccines to aerosol-transmitted intracellular bacterial pathogens. The objective of this application, which is an important step toward this goal, is to determine the role of antibody (Ab)-mediated immunity to lipopolysaccharide (LPS) in protection against pulmonary infection with aerosolized C. burnetii. To achieve this objective, we will test the central hypothesis that immunoglobulins that bind to C. burnetii phase I LPS (PI-LPS) play an important role in protecting vaccinated hosts against Q fever. This hypothesis is based on observations that i) passive transfer of Ab purified from C. burnetii phase I vaccine (PIV)-immunized mice conferred protection against C. burnetii infection in naive recipient mice, and ii) PI-LPS conferred protection against C. burnetii challenge. To test this hypothesis, this proposal focuses on identifying antigens targeted by protective Ab and understanding the mechanisms of Ab-mediated protective immunity against aerosolized C. burnetii. The proposal has two specific aims: Aim 1: to identify antigens targeted by protective Ab. We will identify the protective Ab-recognized antigens and determine if C. burnetii PI-LPS is the key protective antigen responsible for PIV-induced protection. Aim 2: to determine the mechanisms of Ab-mediated protection against pulmonary C. burnetii challenge. We will determine i) if protective Ab activates complement and thus lysis of extracellular C. burnetii, ii) if Ab-mediated protection depends on Fc receptor-mediated effector functions, iii) if Ab-opsonized C. burnetii enhances macrophage phagocytosis, iv) IFN-? is required for Ab-mediated clearance of intracellular C. burnetii and v) if Ab-mediated protection requires help from T cells and to identify the T cell types that are important for Ab-mediated protection. As an outcome of this research, we expect to determine if PI-LPS is a target in protection against Q fever and to understand the contribution of humoral and cellular immunity in vaccine-induced protective immunity against C. burnetii infection. This is expected to have significant positive effects on human (and animal) health, because it will provide information for vaccine design and Ab-based immunotherapeutic strategies for Q fever, and in turn lead to development of new strategies to interfere with aerosol transmission of other dangerous intracellular bacterial pathogens. PUBLIC HEALTH RELEVANCE: Coxiella burnetii is an understudied category B bioterrorist agent that causes acute Q fever and chronic infections in humans. To fill the fundamental gap in knowledge regarding the mechanisms of protective immunity and to develop a safe and effective vaccine against Q fever, this proposal focuses on identifying the antigenic targets that recognize the protective antibody and understanding the mechanisms of antibody-mediated protective immunity against C. burnetii aerosol infection.

描述（由申请方提供）：贝氏柯克斯体是一种专性细胞内革兰氏阴性细菌，可引起世界范围的人畜共患病Q热。人类自然感染通常通过吸入感染性气溶胶发生，临床表现为非典型肺炎，并可发展为严重的致命慢性疾病。C.贝氏体是一种未充分研究的B类选择因子，在美国没有许可的疫苗。建立一种安全有效的疫苗来预防人类Q热是一个重要的公共卫生和国家生物安全目标。该计划的长期目标是开发新的方法来发现安全，有效的疫苗气溶胶传播的细胞内细菌病原体。本申请的目的是确定抗体（Ab）介导的对脂多糖（LPS）的免疫在对抗雾化C.伯内特氏菌为了达到这一目的，我们将测试中心假设，即结合C。贝氏I相LPS（PI-LPS）在保护接种宿主抵抗Q热中起重要作用。该假设基于以下观察：i）从C.贝氏I期疫苗（PIV）免疫的小鼠赋予针对C. ii）PI-LPS赋予针对C. Burnetii挑战。为了验证这一假设，本研究的重点是鉴定保护性Ab所针对的抗原，并了解Ab介导的针对雾化C.伯内特氏菌该提案有两个具体目标：目标1：鉴定保护性Ab靶向的抗原。我们将鉴定保护性Ab识别的抗原，并确定C。贝氏体PI-LPS是负责PIV诱导的保护的关键保护性抗原。目的2：探讨Ab介导的肺保护作用机制。Burnetii挑战。我们将确定i）保护性Ab是否激活补体并因此裂解细胞外C。ii）如果Ab介导的保护依赖于Fc受体介导的效应子功能，iii）如果Ab调理的C.贝氏菌增强巨噬细胞吞噬作用，iv）IFN-？是Ab介导的细胞内C清除所必需的。贝氏体和v）Ab介导的保护是否需要T细胞的帮助，并鉴定对Ab介导的保护重要的T细胞类型。作为本研究的结果，我们希望确定PI-LPS是否是预防Q热的靶点，并了解体液和细胞免疫在疫苗诱导的针对C的保护性免疫中的贡献。贝氏体感染预计这将对人类（和动物）健康产生显著的积极影响，因为它将为Q热的疫苗设计和基于Ab的免疫策略提供信息，进而导致开发新的策略来干扰其他危险的细胞内细菌病原体的气溶胶传播。公共卫生关系：贝氏柯克斯体是一种未充分研究的B类生物恐怖分子制剂，可引起人类急性Q热和慢性感染。为了填补保护性免疫机制方面的知识空白，并开发安全有效的Q热疫苗，本提案侧重于识别识别保护性抗体的抗原靶标，并了解抗体介导的针对C的保护性免疫的机制。贝氏气溶胶感染