Aging with Chronic Viral Infections and the Impact on Innate Immune Responses

描述（由申请人提供）：随着人口老龄化和慢性肝病日益成为发病率和死亡率的重要原因，迫切需要提高我们对慢性病毒感染期间先天和适应性免疫反应动力学的理解，以及这些反应与病毒清除的关系。由于先天免疫反应是抵御病原体的第一道防线，因此阐明衰老如何改变先天免疫并有助于慢性病毒的持续存在是必要的。浆细胞样树突状细胞（pDCs）在检测外来病原体中起着关键作用，是暴露于病毒感染或toll样受体9 （TLR9）或TLR7特异性配体后1型IFN的主要来源。本研究的目的是研究慢性病毒感染对pDC细胞功能的影响，以及这些影响如何影响病毒的持久性和对继发性感染的易感性。我的博士和博士后研究重点是病毒感染期间的先天和适应性免疫反应，取得了令人印象深刻的发表记录。我熟练掌握我目前的研究计划中概述的研究技术。虽然我的初步工作集中在急性病毒感染，我的建议旨在研究慢性病毒感染如何影响先天抗病毒免疫反应与年龄。这一新颖的研究领域对慢性病毒感染日益加重的老龄化人口具有重要的临床意义。本提案中概述的实验结果将为慢性病毒感染期间衰老对先天免疫反应的影响提供见解。最后，我设想这项提议的工作将作为一个跳板，开启我作为一个独立资助的科学家的职业生涯。在继续直接计划和执行实验的过程中，我对生物医学研究的批判性思考能力将进一步提高，并将产生更多的假设，这些假设可以作为未来资助申请的一部分进行测试（例如，R01）。我坚信我有能力和动力成为一名成功的衰老研究者，我坚信我在衰老和免疫方面的工作将有助于理解和治疗慢性病毒感染。获得K01指导研究科学家发展奖将使我能够实现我的主要职业目标，即成为衰老和病毒免疫领域的专家和领导者，通过专注于衰老与免疫反应改变之间的复杂关系，将做出重要的研究贡献，最终转化为改善老年人的功能状态。在我的主要导师团队的指导下，我组织了以下职业发展活动来支持我的主要职业目标。通过我迄今为止的学术训练和工作经验，我已经获得了将免疫学方法应用于衰老研究的必要基础。鉴于这一坚实的基础，我计划将我的培训重点放在操作方面，将我的大部分时间花在实践研究培训上，并针对目前缺乏的特定领域进行高度集中的教学培训。因此，我所提出的职业发展计划旨在为我提供必要的工具，使我成为一名在老龄化领域具有高度竞争力的独立研究人员。除了我将从执行研究计划和与导师团队的互动中获得经验外，我还提出了在奖励期的前两年具体的课程工作，这将有助于我实现短期和长期目标。

DESCRIPTION (provided by applicant): With an aging population and chronic liver disease becoming an increasingly significant cause of morbidity and mortality, there is an urgent need to improve our understanding of the dynamics of innate and adaptive immune responses during chronic viral infection and the relationship of these responses to viral clearance. As the innate immune response is the first line of defense against pathogens, it is imperative to elucidate how aging modifies innate immunity and contributes to chronic viral persistence. Plasmacytoid dendritic cells (pDCs) play a pivotal role in detection of foreign pathogens and represent a major source of type 1 IFN post exposure to viral infections or Toll-Like Receptor 9 (TLR9) or TLR7 specific ligands. The goal of this proposal is to examine the effects of chronic viral infection on pDC cell function and how these effects contribute to viral persistence and susceptibility to a secondary infection. My doctoral and post-doctoral research that focused on innate and adaptive immune responses during viral infection led to an impressive publication record. I am skilled in the research techniques outlined in my current research proposal. While my preliminary work focused on acute viral infection, my proposal aims to investigate how chronic viral infections influence innate antiviral immune responses with aging. This novel field of investigation has important clinical relevance for an aging population increasingly burdened with chronic viral infection. Results from the experiments outlined in this proposal will provide insight on the influence of aging on innate immune responses during chronic viral infections. Lastly, I envision the proposed work to serve as a spring board that will launch a career as an independently funded scientist. In continuing to directly plan and execute experiments, my ability to think critically about biomedical investigation will be further refined and will lead to additional hypotheses which can be tested as part of a future grant application (e.g., R01). I resolutely believe that I have the talent and motivation to become a successful investigator in aging and I strongly believe that my work in aging and immunity will help in the understanding and treatment of chronic viral infections. Receipt of a K01 Mentored Research Scientist Development Award will allow me to achieve my primary career goal of becoming an expert and leader in the field of aging and viral immunity, who, by focusing on the complex relationship between aging and altered immune responses, will make important research contributions that will ultimately translate into improving the functional status of older persons. Under the guidance of my primary mentorship team, I have structured the following career development activities to support my primary career goal. Through my academic training and work experiences to date, I have obtained the essential underpinnings for applying immunologic methods to aging research. Given this strong foundation, I plan to focus on the operational side of my training, spending the largest proportion of my time with hands-on research training, complemented by highly focused didactic training targeting specific areas that are currently deficient. Therefore, the proposed career development plan is designed to give me the required tools to develop into a highly competitive, independent researcher in the field of aging. In addition to the experience that I will gain from executing the research plan and interacting with the mentorship team, I have proposed specific course work through the first two years of the award period that will help me short-term and long-term goals. PUBLIC HEALTH RELEVANCE: At present, over 170 million people are infected by hepatitis C virus (HCV) (1). Acute HCV infection is asymptomatic, making the early stages of infection very difficult to diagnose. A hallmark feature of HCV infection is its tendency towards becoming a persistent, chronic infection, with at least 75% of acute infections becoming chronic. Chronic infection is often associated with significant liver disease, especially chronic active hepatitis, cirrhosis, and hepatocellular carcinoma (1). Chronic liver disease and cirrhosis are the tenth leading causes of death in the United States (2). As life expectancy in developed countries continues to increase, so has the number of elderly patients who have liver disease, with the most common cause of chronic liver disease being HCV (57% of cases) (2). With an aging population and chronic liver disease becoming an increasingly significant cause of morbidity and mortality, there is an urgent need to improve our understanding of the dynamics of innate and adaptive immune responses during chronic viral infection and the relationship of these responses to viral clearance. As the innate immune response is the first line of defense against pathogens, it is imperative to elucidate how aging modifies innate immunity and contributes to chronic viral persistence. Plasmacytoid dendritic cells (pDCs) play a pivotal role in detection of foreign pathogens and represent a major source of type 1 IFN post exposure to viral infections or Toll-Like Receptor 9 (TLR9) or TLR7 specific ligands. Our preliminary experiments investigated whether aging affects innate pDC function during acute viral infection. Our results demonstrate that aged pDCs manifest defective TLR9 primary immune responses during acute viral infection. Impaired pDC function in aged hosts results in decreased production of type 1 IFNs as well as increased mortality and morbidity during HSV-2 viral infection. The goal of this proposal is to examine the effects of chronic viral infection on pDC cell function and how these effects contribute to viral persistence and susceptibility to a secondary infection. Specifically, we will employ murine models to test the hypothesis that aging decreases innate anti-viral immune responses and thereby contributes to the establishment and persistence of chronic viral infections.