Collaborative cross mice as a new model for diverse human outcomes of St. Louis encephalitis virus disease

协作杂交小鼠作为圣路易斯脑炎病毒病多种人类结果的新模型

• 批准号: 10726431
• 负责人: Lark L Coffey
• 金额: $ 25.32万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726431
• 关键词: Americas; Animals; Antibody titer measurement; Biological Response Modifiers; Blocking Antibodies; Blood; Brain; Bypass; Cells; Central Nervous System; Central Nervous System Diseases; Cessation of life; Clinical; Culicidae; Development; Disease; Disease Outbreaks; Disease Outcome; Disease model; Dose; Ebola; Encephalitis; Exhibits; Fever; Flavivirus; Gene Expression; Gene Expression Profiling; Genes; Genetic Determinism; Genetic Variation; Goals; Human; Human Genetics; IFNAR1 gene; Immune; Immune response; Immunocompetent; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Immunophenotyping; Inbred Mouse; Inbreeding; Infection; Influenza; Innate Immune Response; Interferon Receptor; Interferon alpha; Interferons; Intervention; Kidney; Kinetics; Lesion; Link; Measures; Mediating; Mediator; Modeling; Mus; Mutation; Natural Immunity; Outcome; Pathogenesis; Pathology; Periodicals; Persons; Phenotype; Population; Powassan virus; Predisposition; Property; Proteins; Recombinant Inbred Strain; Recombinants; Reproducibility; Role; Serial Passage; Serum; Severities; Severity of illness; Signal Transduction; Spleen; St. Louis Encephalitis Virus; Testing; Therapeutic; Time; Tissues; Translating; Tropism; Vaccines; Viral; Virus; Virus Diseases; West Nile virus; ZIKA; Zoonoses; animal tissue; cohort; cytokine; experience; human disease; human model; immunological diversity; innate immune mechanisms; long-term sequelae; mosquito-borne; mouse model; nervous system disorder; neurovirulence; novel; receptor; response; sensor; tool; transmission process; vaccine candidate; viral genomics; virus genetics; virus host interaction

PROJECT ABSTRACT St. Louis encephalitis virus (SLEV) is a re-emerging mosquito-borne flavivirus that causes a spectrum of manifestations in people ranging from febrile illness to encephalitis and death. Clinical disease caused by SLEV is indistinguishable from related West Nile virus (WNV). Although critical for understanding disease and evaluating countermeasures, current SLEV mouse models are limited in several ways. Prior studies used inbred or immunodeficient mice restricting assessment of the role of innate immunity, intracranial inoculation that artificially bypasses neuroinvasion, and virus strains that were serially passaged in mouse brains which artificially selects for neurovirulence. Compared to inbred or immunodeficient mice, recombinant mice better represent of human genetic diversity which can translate to similar disease to humans. Recombinant Collaborative Cross (CC) mice that were generated from a panel of 8 recombinant inbred strains represent the myriad of outcomes in people infected with the flaviviruses Zika, Powassan, and WNV. WNV-infected CC mice develop a spectrum of outcomes including asymptomatic, symptomatic with central nervous system (CNS) disease, and asymptomatic with CNS disease, where the innate immune response is the major mediator of protection from CNS disease. To circumvent limitations of existing SLEV mouse models, the goal of this project is to develop immunocompetent recombinant CC mouse models of SLEV. We hypothesize that CC mice model human SLEV including to produce clinical disease, viral tropism, and kinetics that parallel the spectrum of human SLEV outcomes, and that protection from CNS disease associates with robust innate immune responses manifest as higher expression or levels of interferon stimulated genes including the antiviral sensor RIG-I and effector cytokines including interferons (IFN)-α/β/γ. These hypotheses will be tested in two project Aims. Aim 1: Define SLEV clinical disease and viral tropism and kinetics in CC mice. We will use CC strains that manifest variable WNV outcomes and inoculate animals via the footpad with a SLEV mosquito- transmitted doses. We will assess clinical disease, infection kinetics and tropism, and viral genomic changes that associate with neuroinvasion. Aim 2: Link elevated innate immune responses to control of SLEV CNS disease in CC mice. We will measure innate responses via gene expression analyses and levels of signaling and secreted effector proteins and correlate these changes with clinical disease, virus levels in blood and target tissues, and histopathologic lesions in the brain. Augmented disease in CC mice treated with IFN- receptor blocking antibody will support IFN signaling as the mediator of protection. This project will develop new human-relevant mouse models of SLEV which can be further used to study the spectrum of pathogenesis, define virus-host interactions and host genetic determinants of susceptibility and severity, test interventions like therapeutics and candidate vaccines, and rapidly adapt to model disease for other new or re-emerging encephalitic flaviviruses.

项目摘要 圣路易斯脑炎病毒（SLEV）是一种重新出现的蚊子传播的黄病毒，会导致一系列 从高温疾病到脑炎和死亡的人的表现。由 SLEV与相关的西尼罗河病毒（WNV）没有区别。虽然对于理解疾病和 评估对策，当前的SLEV鼠标模型受到多种方式受到限制。先前的研究使用了 近交或免疫缺陷的小鼠限制了对先天免疫学，颅内接种作用的评估 人为绕过神经入侵和在小鼠大脑中连续传递的病毒菌株 人为选择神经病毒。与近交或免疫缺陷小鼠相比，重组小鼠更好 重组代表人类遗传多样性，可以转化为与人类类似的疾病。 由8个重组近交菌株产生的协作杂交（CC）小鼠代表 感染了黄病毒寨卡，Powassan和WNV的人们的无数结果。 WNV感染的CC小鼠 发展一系列结果，包括中枢神经系统（CNS）的渐近，症状 疾病，无症状的中枢神经系统疾病，那里的先天免疫反应是 保护CNS病。为了规避现有SLEV鼠标模型的限制，目的是 项目是开发SLEV的免疫能力重组CC小鼠模型。我们假设这一点 CC小鼠模拟人类SLEV，包括产生临床疾病，病毒疗法和动力学，使 人类SLEV结果的范围，并保护与CNS疾病与稳固的先天性相关性 免疫反应表现为较高表达或干扰刺激的水平，包括抗病毒 传感器RIG-I和效应子细胞因子，包括干扰素（IFN）-α/β/γ。这些假设将在两个中进行测试 项目目标。 AIM 1：在CC小鼠中定义SLEV临床疾病和病毒疗法和动力学。我们将使用 CC菌株表现出可变的WNV结果并通过SLEV蚊子通过脚打接种动物 传播剂量。我们将评估临床疾病，感染动力学和疗法以及病毒基因组变化 该与神经入侵相关。目标2：链接升高的先天免疫反应与SLEV CNS的控制 CC小鼠的疾病。我们将通过基因表达分析和信号的水平来测量先天反应 并分泌效应蛋白，并将这些变化与临床疾病，血液中的病毒水平和 目标时机和大脑中的组织病变病变。在接受IFN-治疗的CC小鼠中疾病增强 接收器阻断抗体将支持IFN信号作为保护介质。这个项目将开发 新的与人类相关的SLEV小鼠模型，可进一步用于研究发病机理的光谱， 定义病毒宿主相互作用和易感性和严重程度的宿主遗传决定剂，测试干预措施 治疗剂和候选疫苗，并迅速适应其他新型或重新出现的疾病模型 脑黄病毒。