Control of protective immunity by innate pathways sensing bacterial viability

通过感知细菌活力的先天途径控制保护性免疫

• 批准号: 8528462
• 负责人: Julie Magarian Blander
• 金额: $ 39.83万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528462
• 关键词: Adaptor Signaling Protein; Adjuvant; Agonist; Antibody Formation; Antigens; Area; Attenuated Live Virus Vaccine; Attenuated Vaccines; B-Lymphocytes; Bacteria; Bacterial Infections; Biological Preservation; CD4 Positive T Lymphocytes; Caspase-1; Cells; Characteristics; Detection; Developing Countries; Dose; Drug Formulations; Evolution; Generations; Goals; Hand; IRF3 gene; Immune; Immune response; Immune system; Immunity; Immunization; Inactivated Vaccines; Individual; Infection; Injection of therapeutic agent; Intention; Interferons; Interleukin-1; Life; Link; Mediating; Memory; Messenger RNA; Microbe; Modeling; Molecular; Monitor; Mus; Natural Immunity; Nature; Pathway interactions; Pattern; Phagocytes; Production; Property; Proteins; RNA; Receptor Signaling; Role; Safety; Sterility; T cell response; T-Lymphocyte; TLR3 gene; Tissues; Toll-like receptors; Vaccines; Virulence; Virulence Factors; Work; adaptive immunity; attenuated microorganism; base; cost; design; killings; memory CD4 T lymphocyte; microbial; microorganism; pathogen; receptor; response; signature molecule

DESCRIPTION (provided by applicant): Live attenuated vaccines are long known to induce superior immune protection and lasting immune memory, and with single dose administration in most cases. When compared to their dead counterparts, live vaccines induce a distinct and far more vigorous immune response, triggering an alert mode not warranted for dead microorganisms. But despite the efficacy of live vaccines, several factors have contributed to their lack of popularity. Chief among these are concerns over their safety as well as difficulty and increased cost in their delivery and preservation especially to impoverished areas in developing countries. Understanding the molecular basis for the efficacy of live vaccines would alleviate these concerns, and provide a means to target the relevant pathways that induce optimal protective immunity. The work we propose here is poised to significantly enhance our understanding of the basic immune mechanisms behind the superior efficacy of live attenuated vaccines. We began our work with the hypothesis that innate immune cells sense the most fundamental characteristic of microbial infectivity, microbial viability itself, and activate an immune response tailored to eradicate the infectious threat, and importantly regardless of the presence of specialized factors that regulate microbial virulence. We identified the signature molecule, prokaryotic messenger RNA, which alerts professional phagocytic cells of the innate immune system to the presence of viable microbes in sterile tissues. We identified discrete innate immune responses triggered by the recognition of bacterial viability. We have dissected the innate immune pathways mediating these responses, and determined the identity of the critical Toll-like receptor signaling adaptor that orchestrates these responses. Our goal here is t identify how the alert mode triggered by bacterial viability impacts the subsequent adaptive immune response. With identity of the viability-sensing pathways and the immunostimulatory properties of the bacterial mRNA in hand, we will determine the role of individual players within these pathways in the evolution of the immune response. Unlike previous studies that have used adjuvants and haptenated proteins, we will focus on antigens presented within the context of a bacterial infection. We will investigate both the T cell and B cell immune response beginning first with understanding the nature of the CD4 T cell response because of its critical link to the T cell-dependent antibody response. We will next dissect the antibody response to both T cell-dependent and T cell-independent antigens expressed by both live and dead bacteria. We will define how deficiency in the pathways sensing bacterial viability alters the immune response, depriving it of the factors critical for long lasting protective immunity. Our studies have the high potential to reveal the mechanisms behind the superior protection induced by live vaccines, and to create new adjuvants and immunization strategies that combine the efficacy of live vaccines with the safety of dead vaccines.

描述（由申请人提供）：众所周知，减毒活疫苗可诱导卓越的免疫保护和持久的免疫记忆，并且在大多数情况下采用单剂量给药。与死亡的疫苗相比，活疫苗会引发明显且更加强烈的免疫反应，从而引发死亡微生物所不需要的警报模式。尽管活疫苗具有功效，但有几个因素导致其不受欢迎。其中最主要的是对它们的安全性以及运送和保存的难度和成本增加的担忧，特别是在发展中国家的贫困地区。了解活疫苗功效的分子基础将减轻这些担忧，并提供一种针对诱导最佳保护性免疫的相关途径的方法。我们在此提出的工作旨在显着增强我们对减毒活疫苗卓越功效背后的基本免疫机制的理解。我们的工作始于这样的假设：先天免疫细胞能够感知微生物感染性的最基本特征，即微生物活力本身，并激活专门针对消除感染威胁的免疫反应，而且重要的是，无论是否存在调节微生物毒力的特殊因素。我们确定了标志性分子，即原核信使 RNA，它可以向先天免疫系统的专业吞噬细胞发出无菌组织中存在活微生物的警报。我们发现了由细菌活力识别引发的离散先天免疫反应。我们剖析了介导这些反应的先天免疫途径，并确定了协调这些反应的关键 Toll 样受体信号转导适配器的身份。我们的目标是确定细菌活力触发的警报模式如何影响随后的适应性免疫反应。有了细菌 mRNA 的活力传感途径和免疫刺激特性的鉴定，我们将确定这些途径中个体参与者在免疫反应进化中的作用。与之前使用佐剂和半抗原的研究不同，我们将重点关注细菌感染背景下呈现的抗原。我们将研究 T 细胞和 B 细胞免疫反应，首先了解 CD4 T 细胞反应的性质，因为它与 T 细胞依赖性抗体反应至关重要。接下来我们将剖析对活细菌和死细菌表达的 T 细胞依赖性和 T 细胞非依赖性抗原的抗体反应。我们将定义感知细菌活力的途径的缺陷如何改变免疫反应，使其失去对持久保护性免疫至关重要的因素。我们的研究很有可能揭示活疫苗诱导的卓越保护背后的机制，并创造出将活疫苗的功效与死疫苗的安全性结合起来的新佐剂和免疫策略。