Selective Delivery of a novel bacterial adjuvant for multipurpose vaccination

用于多用途疫苗接种的新型细菌佐剂的选择性递送

基本信息

批准号：
8303820
负责人：
Gregoire Stephane Lauvau
金额：
$ 24.99万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303820
关键词：
Accounting Adjuvant Amino Acid Motifs Animals Antigens Autolysin Automobile Driving Bacteria Bacterial Proteins Biological Models Bone Marrow CCL3 gene CD8B1 gene Cell Wall Cells Cytolysis Cytosol Data Dendritic Cells Development Disease Effector Cell Event Exhibits Family Hour Hydrolase Hydrolysis Immune Immune response Immune system Immunity Immunization Immunologic Memory Immunologic Receptors In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Interferon Type I Interferon Type II Interleukin-2 Life Listeria monocytogenes Macrophage Inflammatory Proteins Mass Spectrum Analysis Mediating Mediator of activation protein Memory Microbe Molecular Monitor Mus Myelogenous Nucleic Acids Organism Outcome Pathway interactions Pattern Pattern recognition receptor Peptidoglycan Phagocytes Point Mutation Process Proteins Recruitment Activity Signal Transduction Spleen Stimulus System T cell differentiation T cell response T memory cell T-Lymphocyte TNF gene Testing Translating Vaccinated Vaccination Viral Virulence Factors Work antimicrobial arm chemokine cytokine design granzyme B in vivo interest macrophage microbial mouse model mutant novel novel vaccines pathogen pathogenic bacteria perforin rapid growth receptor research study response sensor tumor

Accounting Adjuvant Amino Acid Motifs Animals Antigens Autolysin Automobile Driving Bacteria Bacterial Proteins Biological Models Bone Marrow CCL3 gene CD8B1 gene Cell Wall Cells Cytolysis Cytosol Data Dendritic Cells Development Disease Effector Cell Event Exhibits Family Hour Hydrolase Hydrolysis Immune Immune response Immune system Immunity Immunization Immunologic Memory Immunologic Receptors In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Interferon Type I Interferon Type II Interleukin-2 Life Listeria monocytogenes Macrophage Inflammatory Proteins Mass Spectrum Analysis Mediating Mediator of activation protein Memory Microbe Molecular Monitor Mus Myelogenous Nucleic Acids Organism Outcome Pathway interactions Pattern Pattern recognition receptor Peptidoglycan Phagocytes Point Mutation Process Proteins Recruitment Activity Signal Transduction Spleen Stimulus System T cell differentiation T cell response T memory cell T-Lymphocyte TNF gene Testing Translating Vaccinated Vaccination Viral Virulence Factors Work antimicrobial arm chemokine cytokine design granzyme B in vivo interest macrophage microbial mouse model mutant novel novel vaccines pathogen pathogenic bacteria perforin rapid growth receptor research study response sensor tumor

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项目摘要

DESCRIPTION (provided by applicant): Adjuvants are critical molecules involved in driving protective immune responses in vivo. They exhibit strong proinflammatory effects, are often derived from pathogens -in such case they are defined as pathogens associated molecular patterns (PAMPs)- and possess all features of "danger" molecules. They are detected as such by the immune system that has evolved a set of immune receptors, the pattern recognition receptors (PRRs), which recognize them. While enormous advances have been made in characterizing multiple adjuvants over the past decade, the molecular mechanisms of their precise effects are still the subject of intense studies. Adjuvant recognition by immune cells leads to a set of critical events that are necessary for optimal T cell priming and differentiation into effector and memory cells. CD8+ T cells which represent a crucial effector arm of the adaptive immune response require such signals for their optimal activation. In fact, the development of a protective immune response against several pathogenic organisms and diseases is dependent on the ability of antigen-specific CD8+ T cells to best differentiate. These cells confer immunity via the expression of various effector mechanisms such as cytolysis of infected cells and release of proinflammatory cytokines and chemokines that recruit and activate innate immune effector cells. The molecular factors that orchestrate CD8+ T cell differentiation are still incompletely defined and depending on the initial stimuli, the outcome of the priming and the functional features of the T cells are different. Adjuvants in fact represent key mediators of such modulation and therefore can orchestrate adaptive immune responses. Mice immunized with the intracellular bacterium Listeria monocytogenes (Lm) develop life-long immunity against a challenge infection by Lm. Using this model system, we established that secretion of the proinflammatory chemokine CCL3 / MIP-1a (Macrophage Inflammatory Protein 1a) by memory CD8+ T cells early during secondary challenge infection is critical for protective immunity either against the same or a distinct (bystander immunity) intracellular pathogen. Recently we found that amongst memory CD8+ T cells, the CCL3+ cells which represent a substantial proportion (~30%) concomitantly express several effector functions such as granzyme B, perforin, IL-2, IFN-g, TNF-a suggesting that they represent multifunctional memory cells. Our current data also suggest that induction of these cells is likely to depend on one bacterial protein, the p60 autolysin, a virulence factor of the bacteria, which functions to digest peptidoglycan (PGN) cell walls. Our working hypothesis proposes that p60 is orchestrating the induction of CCL3+ plurifunctional memory CD8+ T cells which are important for long-term protective immunological memory. The current project will therefore (i) define the function of the Lm-derived p60 protein that controls the induction of protective CD8 memory and (ii) define the intracellular pathways and inflammatory signals triggered by the p60 protein. PUBLIC HEALTH RELEVANCE: This project focuses at characterizing a novel protein adjuvant derived from bacteria. We propose to understand how this adjuvant modulates the immune response to further take advantage of this finding for the design novel vaccine strategies. Our results suggest that this adjuvant protein controls the induction of long-lived cytolytic memory T cells which are critical cells that can mediate pathogens as well as tumors clearance. These cells exhibit all features of memory cells expressing multiple effector functions. Use of this nove adjuvant may allow vaccinating hosts against any microbes or tumors by promoting high levels of immunological memory.

描述（由申请人提供）：佐剂是在体内驱动保护性免疫反应的关键分子。它们表现出强烈的促炎作用，通常来自病原体 - 在这种情况下，它们被定义为病原体相关的分子模式（PAMP），并且具有“危险”分子的所有特征。免疫系统会因此而检测到它们，该免疫系统已经进化了一组免疫受体，即识别它们的模式识别受体（PRR）。尽管在过去十年中表征多个佐剂方面已经取得了巨大的进步，但其精确作用的分子机制仍然是激烈研究的主题。免疫细胞的辅助识别导致一组关键事件，这些事件对于最佳T细胞启动和分化是必需的进入效应器和记忆单元。代表自适应免疫反应的至关重要效应臂的CD8+ T细胞需要此类信号才能最佳激活。实际上，针对多种致病生物和疾病的保护性免疫反应的发展取决于抗原特异性CD8+ T细胞最佳分化的能力。这些细胞通过表达各种效应机制（例如感染细胞的细胞解析）以及促进和激活先天免疫效应细胞的趋化细胞因子和趋化因子的释放来赋予免疫。编排CD8+ T细胞分化的分子因子仍未完全定义，并取决于初始刺激，启动和 T细胞的功能特征是不同的。实际上，佐剂代表了这种调节的关键介体，因此可以协调适应性免疫反应。用细胞内细菌单核细胞增生（LM）免疫的小鼠会产生终身免疫力，以抵抗LM的挑战感染。使用此模型系统，我们确定了促炎性趋化因子CCL3 / MIP-1A（巨噬细胞炎症蛋白1A）的分泌，记忆CD8+ T细胞在继发性挑战感染期间早期对保护性免疫至关重要。最近，我们发现在记忆CD8+ T细胞中，代表大量比例（〜30％）的CCL3+细胞同时表达了几种效应子函数，例如粒酶B，Perforin，IL-2，IL-2，IFN-G，TNF-A，表明它们代表多功能存储细胞。我们当前的数据还表明，这些细胞的诱导可能取决于一种细菌蛋白，p60 autolysin，p60 autolysin是细菌的毒力因子，该蛋白具有消化肽聚糖（PGN）细胞壁的作用。我们的工作假设提出，p60正在策划CCL3+多功能记忆CD8+ T细胞的诱导，这对于长期保护性免疫记忆很重要。因此，当前项目将（i）定义LM衍生的p60蛋白的功能，该蛋白控制诱导保护性CD8存储器，并定义p60蛋白触发的细胞内途径和炎症信号。公共卫生相关性：该项目着重于表征源自细菌的新型蛋白质佐剂。我们建议了解这种辅助者如何调节免疫反应，以进一步利用这一发现的新型疫苗策略。我们的结果表明，该辅助蛋白控制着诱导长寿命的溶细胞记忆T细胞，这些细胞T细胞是可以介导病原体和肿瘤清除率的关键细胞。这些细胞表现出表达多个效应函数的存储单元的所有特征。使用这种Nove佐剂可以通过促进高水平的免疫记忆来允许对任何微生物或肿瘤进行疫苗接种。