Modeling chikungunya virus neuroinvasion and neuropathogenesis in mice

基孔肯雅病毒神经侵袭和小鼠神经发病机制的建模

基本信息

批准号：
10790337
负责人：
VICTORIA K BAXTER
金额：
$ 54.45万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10790337
关键词：
2 year old Alphavirus Americas Animal Model Antiviral Agents Area Arthritogenic Automobile Driving Autopsy Biological Assay Blood - brain barrier anatomy Brain Cells Central Nervous System Central Nervous System Diseases Central Nervous System Infections Chikungunya virus Child Clinical Cognition Disorders Development Disease Emotional Encephalitis Encephalomyelitis Evaluation Future Genetic Variation Gliosis Goals Human Immune Immune response Immunocompetent Immunocompromised Host Immunofluorescence Immunologic Inbred Mouse Infection Inflammation Left Mediating Meningitis Modeling Mouse Strains Mus Nature Neonatal Neurocognitive Neurocognitive Deficit Neurologic Neurologic Deficit Neurologic Examination Neurologic Signs Neuropathogenesis New Territories Pathogenesis Pathologic Pathology Pathology Report Patients Peripheral Population Predisposition Public Health Publishing Recombinants Reporter Reporting Research Resources Route Stains Techniques Testing United States Vaccines Viral Virus Virus Diseases Work behavior test behavioral disinhibition blood-brain barrier permeabilization brain endothelial cell chikungunya infection design digital pathology immunological status interest motor control motor deficit motor impairment mouse model nervous system disorder nervous system infection neurodevelopment neurological pathology neuropathology real-time images regenerative subcutaneous transmission process vector mosquito white matter young adult

项目摘要

PROJECT SUMMARY The alphavirus chikungunya virus (CHIKV) represents a re-emerging public health concern as mosquito vectors spread to new territories. While CHIKV typically induces an arthritogenic disease, up to 16% of cases result in neurological disease such as encephalitis and meningitis. Surviving patients are often left with long-term neurological deficits, including impaired motor control, emotional and behavioral disinhibition, and cognitive disorders. Despite numerous published clinical case and public health impact reports, very little is known about the neuropathogenesis of CHIKV infection. The limited accessibility and minimally regenerative nature of the central nervous system (CNS) create an insurmountable barrier to studying the course of neurological CHIKV infection in humans and require the use of animal models. Mice have been used extensively to study arthritogenic disease induced by CHIKV and neurological disease induced by other alphaviruses, including long-term neurological sequalae. However, almost all mouse studies examining neurological CHIKV infection have utilized neonatal or immunocompromised mice, which do not accurately reflect the neurodevelopmental or immunological status of susceptible human populations. Furthermore, both arthritogenic and neurological disease induced by alphaviruses have been shown to primarily be mediated by the immune response rather than by the virus itself, further necessitating the use of immunocompetent mice. Preliminary work by our group has found that while young adult C57BL/6J mice are susceptible to infection and replicate the CNS pathology reported in humans following intracranial infection, CNS infection cannot be consistently achieved following peripheral inoculation. In contrast, CC041 mice, a Collaborative Cross strain, consistently demonstrate infection of the brain and signs of neurological disease following subcutaneous inoculation, presenting a potential mouse model by which to evaluate neurological disease induced by CHIKV following peripheral infection. This proposal aims to characterize neurological CHIKV infection in CC041 mice following peripheral inoculation and determine whether CC041 mice develop the neurological disease and CNS pathology seen in humans. In Aim 1, we will determine the mechanism and dynamics by which CHIKV infects the brain in CC041 mice. In Aim 2, we will determine whether CC041 mice develop CNS pathology and long-term neurological sequelae similar to human patients following neurological CHIKV infection. Our studies will establish a new neurodevelopmentally- appropriate, immunocompetent mouse model of peripheral CHIKV infection, allowing for future in depth evaluation of the mechanisms driving neurological disease development and by which to test new potential vaccines, antivirals, and host-directed treatments for neurological infection with CHIKV and other alphaviruses.

项目概要甲病毒基孔肯雅病毒 (CHIKV) 作为蚊子媒介代表了重新出现的公共卫生问题传播到新的领域。虽然 CHIKV 通常会诱发关节炎疾病，但高达 16% 的病例会导致神经系统疾病，如脑炎和脑膜炎。幸存的患者往往会留下长期的痛苦神经系统缺陷，包括运动控制受损、情绪和行为去抑制以及认知障碍失调。尽管发表了大量临床病例和公共卫生影响报告，但人们对这方面知之甚少 CHIKV 感染的神经发病机制。有限的可达性和最低限度的再生性质中枢神经系统 (CNS) 为研究神经学 CHIKV 的过程造成了不可逾越的障碍人类感染并需要使用动物模型。小鼠已被广泛用于研究关节炎 CHIKV 引起的疾病和其他甲病毒引起的神经系统疾病，包括长期神经性后遗症。然而，几乎所有检查神经系统 CHIKV 感染的小鼠研究都利用了新生或免疫功能低下的小鼠，不能准确反映神经发育或易感人群的免疫学状态。此外，关节炎和神经系统疾病甲病毒引起的疾病已被证明主要是由免疫反应介导的，而不是由由病毒本身引起，进一步需要使用具有免疫功能的小鼠。我们课题组前期工作已发现虽然年轻的成年 C57BL/6J 小鼠容易受到感染并复制 CNS 病理学据报道，人类颅内感染后，中枢神经系统感染不能始终如一地实现外周接种。相比之下，CC041 小鼠（一种协作交叉品系）始终表现出感染皮下接种后大脑的变化和神经系统疾病的迹象，呈现出潜在的小鼠用于评估外周感染后 CHIKV 诱发的神经系统疾病的模型。这个提议旨在表征 CC041 小鼠外周接种后神经系统 CHIKV 感染并确定 CC041 小鼠是否会出现人类常见的神经系统疾病和中枢神经系统病理学。在目标 1 中，我们将确定 CHIKV 感染 CC041 小鼠大脑的机制和动力学。在目标 2 中，我们将确定 CC041 小鼠是否会出现与人类相似的中枢神经系统病理学和长期神经系统后遗症神经系统 CHIKV 感染后的患者。我们的研究将建立一个新的神经发育- 适当的、具有免疫功能的外周 CHIKV 感染小鼠模型，为未来的深入研究奠定了基础评估驱动神经系统疾病发展的机制并通过其测试新的潜力针对 CHIKV 和其他甲病毒的神经感染的疫苗、抗病毒药物和针对宿主的治疗。