A unique mouse model for studying immunity to virulent Franciscella infections

用于研究对有毒弗朗西斯菌感染的免疫力的独特小鼠模型

• 批准号: 7659141
• 负责人: GARY R. KLIMPEL
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-22 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659141
• 关键词: Aerosols; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; Asia; Attenuated; Attenuated Vaccines; Bacteria; Bacterial Antigens; Bacterial Proteins; Biological; Breathing; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Cessation of life; Coupled; Development; Disease; Dose; Europe; Exposure to; Francisella; Francisella tularensis; Future; Goals; Gram-Negative Bacteria; Host Defense; Human; Humoral Immunities; Immune Sera; Immune response; Immunity; Immunology; Infection; Inhalation Exposure; Knowledge; Learning; Levaquin; Licensing; Medical; Mus; National Security; North America; Nose; Organism; Pathology; Pharmaceutical Preparations; Play; Production; Public Health; Research; Respiratory Tract Infections; Risk; Role; Route; Staining method; Stains; Strategic Planning; T-Lymphocyte; Testing; Tularemia; Vaccines; Virulent; aerosolized; attenuation; combat; immune function; innovation; mouse model; pathogen; pathogenic bacteria; public health relevance; vaccine candidate; vaccine development; weapons

DESCRIPTION (provided by applicant): Francisella tularensis is a gram-negative bacterium and one of the top-priority agents ("Class A") most likely to pose a potential risk to national security. Although much has been learned from a mouse model using an attenuated strain of Francisella, Francisella tularensis live vaccine strain (LVS), little is known about how mice respond to virulent Francisella Type A strains (SCHU S4) with regard to immunity to inhalation exposure. There are few studies of virulent Type A strains of Francisella using mice and/or in mice exposed via inhalation challenge. The immune functions important for protection against intranasal or inhalation exposure to Francisella are still not completely understood or resolved. Studies in the mouse model of LVS have shown that cell-mediated immunity has an important function in host defense, but there is also new and recent evidence that antibodies play an important role in immunity. We recently developed a mouse model to assess development of protective immunity to intra-nasal challenge with virulent Francisella (SCHU S4). Mice challenged intra-nasally with a lethal dose of SCHU S4 and then treated with the drug levofloxacin were not only cured, but also developed protective immunity against intra-nasal re-challenge with SCHU S4. Importantly, we showed that serum from these immune mice protects na¿ve mice from an intra-nasal infection with a lethal dose of SCHU S4. Our overall goal is to test the hypothesis that antibody specific for bacterial proteins can be protective for mice following aerosol challenge with virulent Francisella tularensis (SCHU S4) and that the bacterial antigens recognized by protective antibodies can be used as an effective vaccine. The specific aims to test this hypothesis are as follows: 1) To optimize the protective immunity and antibody responses generated in mice following aerosol challenge with virulent Francisella and treated with levoflloxacin and 2) To identify and characterize the important antigens involved in protection which are identified by antisera generated in mice following aerosol challenge with Francisella and treated with levofloxacin. PUBLIC HEALTH RELEVANCE: Francisella tularensis is a bacterium that is one of the most infectious pathogens known and can be used as a bioweapon against the public via inhalation exposure. Unfortunately, little is currently known about how to protect the public against such a threat. This application will further our knowledge about this bacterium by developing an animal model for investigating future vaccine development

描述（由申请人提供）：土拉热弗朗西丝菌是一种革兰氏阴性细菌，是最有可能对国家安全构成潜在风险的最高优先级病原体之一（“A类”）。尽管已经从使用弗朗西斯菌减毒株（土拉弗朗西斯菌活疫苗株（LVS））的小鼠模型中了解了很多，但关于小鼠对强毒弗朗西斯菌A型菌株（SCHU S4）在吸入暴露免疫方面的反应却知之甚少。很少有使用小鼠和/或通过吸入激发暴露的小鼠对弗朗西斯菌属A型强毒菌株进行研究。免疫功能的重要性，防止鼻内或吸入暴露于弗朗西斯仍然没有完全理解或解决。对LVS小鼠模型的研究表明，细胞介导的免疫在宿主防御中具有重要功能，但最近也有新的证据表明抗体在免疫中发挥重要作用。我们最近开发了一种小鼠模型，以评估对强毒弗朗西斯菌（SCHU S4）鼻内攻击的保护性免疫的发展。用致死剂量的SCHU S4鼻内攻击小鼠，然后用药物左氧氟沙星治疗，不仅治愈了，而且还产生了对SCHU S4鼻内再攻击的保护性免疫。重要的是，我们发现，来自这些免疫小鼠的血清可以保护未经处理的小鼠免受致命剂量的SCHU S4的鼻内感染。我们的总体目标是检验以下假设：对细菌蛋白特异性的抗体可以在用毒性土拉弗朗西斯菌（SCHU S4）气溶胶攻击后对小鼠具有保护性，并且由保护性抗体识别的细菌抗原可以用作有效的疫苗。检验这一假设的具体目的如下：1）优化用强毒弗朗西斯菌气溶胶攻击并用左氧氟沙星处理的小鼠中产生的保护性免疫和抗体应答; 2）鉴定和表征参与保护的重要抗原，所述重要抗原由用弗朗西斯菌气溶胶攻击并用左氧氟沙星处理的小鼠中产生的抗血清鉴定。公共卫生相关性：土拉热弗朗西丝菌是一种细菌，是已知的最具传染性的病原体之一，可通过吸入暴露用作针对公众的生物武器。不幸的是，目前对如何保护公众免受这种威胁知之甚少。这一应用将通过开发用于研究未来疫苗开发的动物模型来进一步加深我们对这种细菌的了解