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

项目摘要 虽然现代疗法使3700多万艾滋病毒携带者能够经历接近正常的情况 预期寿命并将其转变为一种可控的慢性病，神经认知障碍仍然是一种 尚未解决的临床问题。越来越多的证据表明，慢性系统免疫激活对 神经炎症，而神经炎症会增加神经退行性疾病的严重程度。 有趣的是，病毒引起的神经炎症与神经退行性疾病有惊人的相似之处，而且是慢性 感染可能会增加患神经退行性疾病的风险。一个与以下因素相关的因素 神经炎症、神经退行性变和宿主对微生物病原体的免疫是免疫激酶 富含亮氨酸重复蛋白激酶2(LRRK2)。LRRK2被认为与调节抗病毒细胞因子活性有关， 增加对分枝杆菌感染的易感性，突变的LRRK2是最常见的单基因 神经退行性疾病帕金森氏症的病因。这项建议的长期目标是 扩大LRRK2在细菌感染过程中调节抗病毒免疫的观察以确定 LRRK2在病毒致病和神经炎症中的作用及评价其治疗潜力。使用 针对HIV的猕猴SIV感染模型，这项提案寻求解决的根本问题是 SIV感染促进LRRK2的表达，以及LRRK2的缺失如何影响SIV的发病机制和宿主 免疫反应。我们推测LRRK2通过调节抗病毒作用参与HIV的发病。 豁免权。为了测试这一点，我们将使用非人灵长类动物(NHP)模型来评估SIV感染对 LRRK2基因在循环免疫人群和胃肠道中的纵向表达和蛋白水平 在大脑的某个时间点，LRRK2在这些组织中动态表达。接下来，我们将 使用体内和体外方法评估LRRK2抑制对SIV宿主反应的影响。这个 该项目获得的数据将有助于阐明LRRK2在抗病毒免疫激活和 为未来的研究提供初步数据，调查病毒诱导的因素 神经炎。拟议的研究和辅导职业发展计划将在杜兰进行 国家灵长类中心(TNPRC)在病毒专家Tracy Fisher和Ronald Veazey博士的指导下 诱导的神经炎症和SIV的发病机制。TNPRC是国家NHP生物医学资源 在病毒发病机制和治疗干预方面有着悠久的研究历史和卓越的研究成果。这个 TNPRC坚定地致力于培训和指导，这体现在广泛的资金、努力- 以计划为基础的支持，为早期阶段培养丰富多样的培训环境 调查人员。K01提供的指导支持和专门的时间将促进Vail博士的职业目标 成为研究宿主病原体相互作用的独立调查者和NHP研究员。

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.