Immune Protection Against Pulmonary Tularemia

针对肺兔热病的免疫保护

基本信息

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
项目类别：
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

项目摘要

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.

指令）：我们的总体目标是开发针对肺兔热病的有效疫苗接种方法。在上一个资助期间，我们取得了相当大的进展，包括证明对 C57BL/6 小鼠针对高毒力 A 型 F. tularensis (Ft)、SchuS4、可以由 i.n 诱导。接种 FcR 靶向灭活 LVS {\Ft)。这是我们的第一个案例灭活疫苗可提供针对 Ft SchuS4 的保护的知识。在这个更新申请后，我们将进一步优化粘膜疫苗接种条件，表征其效果肺部疫苗接种，并定义负责保护性免疫的细胞和体液机制对抗高毒力 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，接种 FcR 靶向免疫原，以增强对 Ft SchuS4 粘膜 (i.n) 攻击的免疫反应和保护水平。二将使用不同的方法将 Ft 靶向 FcR：a) 施用预制的 mAb-IFf 复合物， b)同时接种未复合的Ft加抗-Ff mAb； 2）建立机制通过评估 FcR 靶向组织的分布，负责增强免疫力的诱导和淋巴器官，以确定是否增强了 '\Ft 到次级淋巴组织和 APC 的定位在这些组织内，由于 FcR 靶向而发生。还将确定是否增强\Ft APC 上针对 FcR 的处理和呈现结果； 3）建立效应机制负责在 i.n. 后加强保护FcR 靶向细菌疫苗接种。机制负责粘膜疫苗接种后的保护将通过抗 F/ 的被动转移进行研究向幼鼠提供抗体或细胞，特别注意检查协同作用的潜在要求体液和细胞免疫机制之间诱导有效的保护。的角色诱导期和效应期的 TLR/NLR 和 ROS/RNS 将通过遗传学方法进行检查与子项目 2 和 3 的 PL 协商，确定有缺陷的小鼠和特定的激动剂/拮抗剂。子项目 1 的结果将有助于设计新的粘膜疫苗接种策略，以实现有效的生物防御对抗有毒 Ft 感染，并将为肺部免疫机制提供新的见解负责预防呼吸道兔热病。相关性（参见说明）：该子项目的结果将有助于设计新的粘膜疫苗接种策略，以实现有效的针对有毒 Ft 感染的生物防御，将为肺部免疫提供新的见解负责预防呼吸道兔热病的机制。