Role of LRRK2 in immunity in a nonhuman primate model of SIV

项目摘要 虽然现代疗法已使超过3700万艾滋病毒感染者的经历接近正常 预期寿命并将其转化为可管理的慢性疾病，神经认知障碍仍然是一个 未解决的临床问题。越来越多的证据表明，慢性全身免疫激活有助于 神经炎症，神经炎症促进神经退行性疾病的严重性。 有趣的是，病毒引起的神经炎症与神经退行性疾病有着惊人的相似之处， 感染可能会增加患神经退行性疾病的风险。一个因素与 神经炎症、神经变性和宿主对微生物病原体的免疫是免疫激酶 富含亮氨酸重复序列激酶2（LRRK2）。LRRK2与调节抗病毒细胞因子活性有关， 赋予对分枝杆菌感染的易感性，而突变的LRRK2是最常见的单基因 帕金森氏症的病因。本提案的长期目标是 扩展LRRK2在细菌感染期间调节抗病毒免疫的观察，以确定 LRRK2在病毒发病机制和神经炎症中的功能，并评估其治疗潜力。使用 猕猴SIV感染HIV的模型，该提案旨在解决以下基本问题： SIV感染促进LRRK2表达，以及LRRK2的缺失如何影响SIV发病机制和宿主 免疫反应我们假设LRRK2通过调节抗病毒蛋白的表达而参与HIV的发病机制。 免疫力为了验证这一点，我们将使用非人灵长类动物（NHP）模型来评估SIV感染对 循环免疫群体和胃肠道中LRRK2基因表达和蛋白水平的纵向变化 道，并在单一时间点在大脑中，因为LRRK2在这些组织中动态表达。接下来我们就 使用体内和离体方法评估LRRK2抑制对宿主对SIV应答的影响。的 该项目获得的数据将阐明LRRK2在抗病毒免疫激活中的功能， 为未来的研究提供初步数据，调查导致病毒诱导的 神经炎症拟议的研究和指导职业发展计划将在杜兰大学进行 国家灵长类动物中心（TNPRC）在Tracy Fisher和罗纳德Vezey博士的指导下， 引起的神经炎症和SIV发病机制。TNPRC是NHP生物医学的国家资源 在病毒发病机制和治疗干预方面具有悠久的研究历史。的 TNPRC对培训和指导的坚定承诺体现在广泛的财务，努力- 基础和方案支持，为早期阶段培养丰富多样的培训环境 investigators. K 01提供的指导支持和专门时间将进一步推进Vail博士的职业目标 成为一名独立的研究者和NHP研究人员，研究宿主病原体的相互作用。

Project Summary While modern therapy has enabled the more than 37 million people living with HIV to experience near normal life expectancy and transformed it into a manageable chronic disease, neurocognitive impairment remains an unresolved clinical concern. Increasing evidence indicates that chronic systemic immune activation contributes to neuroinflammation, and neuroinflammation promotes the severity of neurodegenerative diseases. Intriguingly, viral-induced neuroinflammation has striking similarities to neurodegenerative disease, and chronic infection may increase the risk of developing neurodegenerative disease. One factor linked to neuroinflammation, neurodegeneration, and host immunity against microbial pathogens is the immune kinase leucine rich repeat kinase 2 (LRRK2). LRRK2 has been implicated in modulating antiviral cytokine activity, conferring susceptibility to mycobacterial infection, and mutated LRRK2 is the most common monogenetic cause of the neurodegenerative disorder Parkinson’s disease. The long-term objectives of this proposal are to extend the observation that LRRK2 modulates antiviral immunity during bacterial infection to determine the function of LRRK2 in viral pathogenesis and neuroinflammation and assess its therapeutic potential. Using a macaque SIV infection model for HIV, this proposal seeks to address the fundamental questions of whether SIV infection promotes LRRK2 expression, and how loss of LRRK2 impacts SIV pathogenesis and the host immune response. We hypothesize that LRRK2 contributes to HIV pathogenesis through regulation of antiviral immunity. To test this, we will use a non-human primate (NHP) model to assess the impact of SIV infection on LRRK2 gene expression and protein levels longitudinally in circulating immune populations and gastrointestinal tract, and at a single time point in the brain as LRRK2 is dynamically expressed in these tissues. Next, we will assess the impact of LRRK2 inhibition on host response to SIV using both in vivo and ex vivo approaches. The data obtained by this project will shed light on the function of LRRK2 in antiviral immune activation and generate preliminary data for future studies investigating factors contributing to viral-induced neuroinflammation. The proposed study and Mentored Career Development Plan will be conducted at Tulane National Primate Center (TNPRC) under the guidance of Drs. Tracy Fisher and Ronald Veazey, experts in viral induced neuroinflammation and SIV pathogenesis. The TNPRC is a national resource for NHP biomedical research with a long history of research excellence in viral pathogenesis and therapeutic intervention. The TNPRC has a strong commitment to training and mentorship demonstrated by extensive financial, effort- based, and programmatic support to cultivate a rich and diverse training environment for early-stage investigators. The mentored support and dedicated time provided by the K01 will further Dr. Vail’s career goals of becoming an independent investigator and NHP researcher studying host pathogen interactions.