Mechanism of Antibody-mediated Immunity against F. tularensis

土拉弗朗西斯抗体介导的免疫机制

• 批准号: 7788505
• 负责人: Girish S Kirimanjeswara
• 金额: $ 8.68万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788505
• 关键词: Affect; Antibodies; Antibody-mediated protection; Area; Asses; Bacteria; Bordetella; Burkholderia; Cell Communication; Cell physiology; Cells; Chemicals; Chronic Disease; Complement; Confocal Microscopy; Cryptococcus; Data; Ehrlichia; Environment; Enzymes; Event; Fc Receptor; Francisella; Francisella tularensis; Generations; Genes; Genetic Transcription; Genus Mycobacterium; Immune Sera; Immunity; Immunobiology; In Vitro; Interferons; Label; Lead; Leishmania; Life Style; Listeria; Mediating; Mentors; Modeling; Molecular and Cellular Biology; Mycobacterium tuberculosis; Outcome; Outcome Study; Phagocytes; Play; Relative (related person); Research Proposals; Role; Safety; Salmonella; Signal Transduction; System; Therapeutic; Therapeutic Intervention; Training; Tularemia; Vaccines; Virulent; Western Blotting; Yersinia pestis; bactericide; base; career; cell mediated immune response; cytokine; design; extracellular; improved; in vivo; inhibitor/antagonist; killings; macrophage; mouse model; neutrophil; novel; pathogen; prophylactic; protective efficacy; receptor; respiratory; response; trafficking

DESCRIPTION (provided by applicant): Antibodies are thought to have limited protective efficacy against intracellular pathogens since they have restricted access to intracellular compartments. However, growing evidence indicates that specific antibodies play a significant role in conferring sterilizing immunity by a close and critical association with cell-mediated immune responses. The specific mechanisms of the synergistic effect of cell-mediated and humoral responses, however, remain poorly understood. In the case of Francisella tularensis, antibodies together with the cytokine IFN-? were shown to be critical in achieving rapid bacterial elimination in vivo. Furthermore, in vitro data suggest that a rapid intracellular killing of F. tularensis could be achieved if bacteria are opsonized with specific antibodies and are internalized by IFN-?-activated phagocytes. These observations lead to the hypothesis that rapid intracellular killing of intracellular bacteria by phagocytes requires the synergistic effect of IFN-? and Fc? receptor-mediated cellular events. This proposal is designed to investigate the effect of IFN-? on the fate of bacteria internalized via Fc?R by professional phagocytes and enhance the efficacy of antibodies using adjunct cytokines such as IFN-? therapy with the following specific aims: I) to determine intracellular RNS and ROS dependent bactericidal mechanisms that lead to rapid killing of opsonized F. tularensis by IFN-?- activated phagocytes, II) To determine the Fc?R- and IFN-?R-dependent signaling events leading to RNS and ROS generation by IFN-?-activated macrophages following internalization of opsonized F. tularensis, and III) to establish the trafficking of opsonized F. tularensis to various intracellular compartments of IFN-?-activated phagocytes. The results obtained will advance our understanding of interactions between humoral and cell-mediated immune responses against intracellular pathogens. The potential applications of the outcome of the study may include the design of novel prophylactic and therapeutic strategies not only against F. tularensis, but also other intracellular bacteria such as M. tuberculosis and L. pneumophila. The proposed study will also facilitate training of PI in the areas of cell and molecular biology and its application in mucosal immunobiology, areas of immediate and long term career objectives, respectively, of the candidate. The proposal and research environment at the mentor's lab complements the PI's desire to utilize basic understanding of cellular processes for therapeutic applications. There are no vaccines available against Francisella tularensis and antibody-based therapies have limited efficacy against extremely virulent form of the bacteria, the form most likely to be used by bioterrorists. We have discovered that addition of cytokine with antibodies provide improved protection and the current proposal is designed to understand the mechanism of synergy between antibodies and cytokines. These studies will result in the design of novel adjunct pharmacological agents to improve the antibody-based therapies against various bacterial pathogens.

描述（由申请人提供）：抗体被认为对细胞内病原体具有有限的保护疗效，因为它们限制了细胞内隔室的机会。然而，越来越多的证据表明，特定抗体在通过与细胞介导的免疫反应的紧密相关和关键关联来赋予免疫力中起重要作用。然而，细胞介导的和体液反应的协同作用的特定机制仍然很少了解。在francisella tularensis的情况下，抗体以及细胞因子IFN-？事实证明，在体内实现快速细菌消除至关重要。此外，体外数据表明，如果细菌用特定的抗体调子并被ifn - ？ - ？ - 激活的吞噬细胞内化，则可以快速地细胞内杀死tuarlensis。这些观察结果导致了一个假设，即吞噬细胞对细胞内细菌的快速杀死需要IFN-的协同作用？和FC？受体介导的细胞事件。该建议旨在研究IFN-的效果？在通过专业吞噬细胞通过FC？R内化的细菌的命运上，并使用辅助细胞因子（例如IFN-）增强了抗体的功效？ therapy with the following specific aims: I) to determine intracellular RNS and ROS dependent bactericidal mechanisms that lead to rapid killing of opsonized F. tularensis by IFN-?- activated phagocytes, II) To determine the Fc?R- and IFN-?R-dependent signaling events leading to RNS and ROS generation by IFN-?-activated macrophages following internalization of opsonized F. tularensis和iii）建立了对tuarlensis的转运f。to骨的运输，以供IFN-？ - ？ - 激活的吞噬细胞的各种细胞内室。获得的结果将提高我们对针对细胞内病原体的体液和细胞介导的免疫反应之间相互作用的理解。该研究结果的潜在应用可能包括设计新型预防性和治疗性策略，不仅针对F. toarlensis，还针对其他细胞内细菌（如结核分枝杆菌和肺炎乳杆菌）的设计。拟议的研究还将促进PI在细胞和分子生物学领域的培训及其在粘膜免疫生物学中的应用，分别是候选人的直接和长期职业目标领域。导师实验室的建议和研究环境补充了PI利用对治疗应用的基本理解的愿望。 没有针对Francisella tolarensis的疫苗，基于抗体的疗法对细菌的极具毒性形式的疗效有限，这种形式最有可能被生物恐怖主义者使用。我们已经发现，添加抗体的细胞因子可提供改进的保护，目前的建议旨在了解抗体和细胞因子之间的协同作用。这些研究将导致新型辅助药理学剂的设计，以改善针对各种细菌病原体的抗体疗法。

项目成果

Development of a novel Francisella tularensis Live Vaccine Strain expressing ovalbumin provides insight into antigen-specific CD8+ T cell responses.

表达卵清蛋白的新型土拉弗朗西斯菌活疫苗株的开发提供了对抗原特异性 CD8 T 细胞反应的深入了解。

• DOI: 10.1371/journal.pone.0190384
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Place,DavidE;Williamson,DavidR;Yuzefpolskiy,Yevgeniy;Katkere,Bhuvana;Sarkar,Surojit;Kalia,Vandana;Kirimanjeswara,GirishS
• 通讯作者: Kirimanjeswara,GirishS