Immune Protection Against Pulmonary Tularemia

针对肺兔热病的免疫保护

• 批准号: 8226311
• 负责人: DENNIS W METZGER
• 金额: $ 53.62万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226311
• 关键词: Agonist; Alveolar Macrophages; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Attention; Attenuated Vaccines; Bacteria; C57BL/6 Mouse; Cells; Cellular Immunity; Complex; Consultations; Enzymes; Event; Fc Receptor; Fluorescence Microscopy; Francisella tularensis; Funding; Generations; Immune; Immune response; Immunity; Immunobiology; Immunohistochemistry; Inactivated Vaccines; Infection; Interleukin-12; Investigation; Life; Lung; Lymphocyte Subset; Lymphoid Tissue; Macrophage Activation; Mediating; Molecular; Mouse Strains; Mus; Natural Immunity; Organ; Oxidants; Pathogenesis; Phase; Principal Investigator; Process; Role; Secondary to; Therapeutic Uses; Time; Tissues; Tularemia; Vaccinated; Vaccination; Vaccine Adjuvant; Virulent; adaptive immunity; arm; base; biodefense; cytokine; design; infancy; insight; killings; mucosal vaccination; mutant; novel; programs; prophylactic; pulmonary vaccination; respiratory; response; success; tool; trafficking; vaccination strategy

instmctions): Our overall objective is to develop approaches for effective vaccination against pulmonary tularemia. During the previous funding period, we made considerable progress, including the demonstration that significant protection in C57BL/6 mice against the highly virulent type A strain of F. tularensis {Ft), SchuS4, can be induced by i.n. inoculation of FcR-targeted inactivated LVS {\Ft). This is the first case to our knowledge in wliich an inactivated vaccine has provided protection against Ft SchuS4. In this renewal application, we will further optimize conditions for mucosal vaccination, characterize the effects of pulmonary vaccination, and define the cellular and humoral mechanisms responsible for protective immunity against the highly virulent type A strain, SchuS4. Specifically, we will: 1) Determine the ability of i.n. vaccination with FcR-targeted immunogens, in the absence or presence of exogenous IL-12, to enhance the immune response to, and levels of protection against, mucosal (i.n.) challenge with Ft SchuS4. Two separate approaches will be used to target \Ft to FcR: a) administration of preformed mAb-IFf complexes, and b) simultaneous inoculation of uncomplexed \Ft plus anti-Ff mAb; 2) Establish the mechanisms responsible for enhanced induction of immunity by assessing the distribution of FcR targeted \Ft to tissues and lymphoid organs to determine if enhanced localization of '\Ft to secondary lymphoid tissues, and APC within these tissues, occurs as a result of FcR targeting. It will also be determined if enhanced \Ft processing and presentation results from targeting to FcR on APC; and 3) Establish the effector mechanisms responsible for enhanced protection after i.n. vaccination with FcR-targeted bacteria. The mechanisms responsible for protection after mucosal vaccination will be investigated by passive transfer of anti-F/ antibody or cells to naive mice with particular attention paid to examining a potential requirement for synergy between humoral and cellular immune mechanisms for induction of effective protection. The roles of TLR/NLRs and ROS/RNS in both inductive and effector phases will be examined by using genetically deficient mice and specific agonists/antagonists, in consultation with the PLs of subprojects 2 and 3. The results of subproject 1 will allow the design of new mucosal vaccination strategies for effective biodefense against infection with virulent Ft and will provide novel insight into the pulmonary immune mechanisms that are responsible for protection against respiratory tularemia. RELEVANCE (See Instruct'ons): The results of this subproject will allow the design of new mucosal vaccination strategies for effective biodefense against infection with virulent Ft and will provide novel insight into the pulmonary immune mechanisms that are responsible for protection against respiratory tularemia.

Instmctions）： 我们的总体目标是开发有效疫苗接种肺部血症的方法。 在上一个资金期间，我们取得了相当大的进步，包括 C57BL/6小鼠的显着保护对高毒的A型菌株（tularensis {ft），schus4， 可以由I.N.诱导接种FCR靶向的灭活LVS {\ ft）。这是我们的第一个情况 灭活的疫苗的知识为FT Schus4提供了保护。在这个 更新应用，我们将进一步优化粘膜疫苗接种条件，表征 肺疫苗接种，并定义负责保护性免疫的细胞和体液机制 针对高毒A型菌株Schus4。具体来说，我们将：1）确定I.N.的能力。 在不存在或存在外源性IL-12的情况下，用FCR靶向免疫原的疫苗接种，以增强 对FT SCHUS4的粘膜（I.N.）挑战的免疫反应和保护水平。二 将使用单独的方法将\ ft靶向FCR：a）预先形成的mab-iff复合物的给药， b）同时接种无复杂的\ ft加抗ff mAb； 2）建立机制 负责通过评估靶向\ ft的分布到组织来增强免疫力的诱导诱导 和淋巴器官，以确定“ \ ft的定位”是否增强了二次淋巴组织和APC 在这些组织中，由于FCR靶向而发生。如果增强\ ft，也将确定 对APC的靶向FCR的处理和表现结果； 3）建立效应器机制 负责在I.N.之后增强保护用FCR靶向细菌疫苗接种。机制 粘膜疫苗接种后负责保护，将通过被动转移抗F/ 对天真小鼠的抗体或细胞，特别注意检查协同作用的潜在需求 在诱导有效保护的体液和细胞免疫机制之间。角色 电感和效应阶段中的TLR/NLR和ROS/RN将通过遗传学检查。 与小鼠和特定的激动剂/拮抗剂与第2和3号的PLS协商。 第1个副本的结果将允许设计新的粘膜疫苗接种策略，以实现有效生物化。 反对用强烈的FT感染，并将提供对肺免疫机制的新见解 负责保护呼吸道血症。 相关性（请参阅指示）： 该子项目的结果将允许设计新的粘膜疫苗接种策略以有效 抗强化FT感染的生物粘液素，并将为肺免疫提供新的见解 负责保护呼吸道血症的机制。