Control of protective immunity by innate pathways sensing bacterial viability

描述（由申请方提供）：长期以来已知减毒活疫苗可诱导上级免疫保护和持久免疫记忆，并且在大多数情况下单次给药。与死亡疫苗相比，活疫苗诱导的免疫反应明显更强，引发的警报模式对死亡微生物来说是不必要的。但是，尽管活疫苗有效，但有几个因素导致它们不受欢迎。其中最主要的问题是对它们的安全以及运送和保存的困难和成本增加的关切，特别是对发展中国家贫困地区的关切。了解活疫苗有效性的分子基础将缓解这些担忧，并提供一种靶向诱导最佳保护性免疫的相关途径的方法。我们在这里提出的工作是准备显着提高我们的理解的基本免疫机制背后的上级效力的减毒活疫苗。我们的工作始于这样一个假设，即先天免疫细胞感知微生物感染性的最基本特征，即微生物本身的活力，并激活一种免疫反应，以消除感染性威胁，重要的是，无论是否存在调节微生物毒力的专门因素。我们确定了标志性分子，原核信使RNA，它提醒先天免疫系统的专业吞噬细胞在无菌组织中存在活微生物。我们确定了由识别细菌活力触发的离散先天免疫应答。我们已经解剖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样受体信号转导衔接子的身份。我们的目标是确定由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。随着生存力传感途径和细菌mRNA的免疫刺激特性的确定，我们将确定这些途径中的个体参与者在免疫应答演变中的作用。与以前使用佐剂和半抗原化蛋白质的研究不同，我们将关注细菌感染背景下呈递的抗原。我们将研究T细胞和B细胞免疫应答，首先从理解CD4 T细胞应答的性质开始，因为其与T细胞依赖性抗体应答的关键联系。接下来，我们将分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应答。我们将定义如何在传感细菌活力的途径缺陷改变免疫反应，剥夺它的长期持久的保护性免疫的关键因素。我们的研究具有很高的潜力，以揭示背后的机制，由活疫苗诱导的上级保护，并创造新的佐剂和免疫策略，结合联合收割机的活疫苗的有效性与死疫苗的安全性。

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.