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.

项目摘要 Alphavirus Chikungunya病毒（CHIKV）代表了作为蚊子向量的重新出现的公共卫生问题传播到新领土。 CHIKV通常诱导关节疾病，但多达16％的病例导致神经疾病，例如脑炎和脑膜炎。幸存的患者经常长期留下神经系统缺陷，包括运动控制受损，情绪和行为抑制以及认知能力疾病。尽管有许多已发表的临床病例和公共卫生影响报告，但对 CHIKV感染的神经病发生。有限的可访问性和最小的再生性质中枢神经系统（CNS）为研究神经系统CHIKV的过程创造了一个无法克服的障碍人类感染，需要使用动物模型。小鼠已被广泛用于研究关节作用由CHIKV引起的疾病和其他α病毒引起的神经系统疾病，包括长期神经系统序列。但是，几乎所有检查神经chikv感染的小鼠研究都使用了新生儿或免疫功能低下的小鼠，这些小鼠无法准确反映神经发育或易感人群的免疫学地位。此外，关节型和神经学都已证明由α病毒诱导的疾病主要是由免疫反应介导的，而不是通过病毒本身，进一步需要使用免疫能力的小鼠。我们小组的初步工作发现年轻的成年C57BL/6J小鼠容易感染并复制CNS病理学颅内感染后的人类报道，CNS感染不能始终如一地达到外围接种。相比之下，协作交叉应变CC041小鼠始终证明感染皮下接种后的大脑和神经系统疾病的迹象，呈现潜在的小鼠通过该模型评估周围感染后CHIKV引起的神经系统疾病。这个建议旨在表征周围接种后CC041小鼠中神经系统CHIKV感染并确定 CC041小鼠是否发展在人类中看到的神经系统疾病和CNS病理学。在AIM 1中，我们将确定CHIKV感染CC041小鼠大脑的机制和动力学。在AIM 2中，我们将确定CC041小鼠是否发展为CNS病理学和长期神经后遗症神经系统CHIKV感染后的患者。我们的研究将建立一个新的神经发育外围chikv感染的适当，免疫功能的小鼠模型，可深入评估驱动神经疾病发展的机制，并通过它测试新的潜力疫苗，抗病毒药和宿主指导的治疗方法，用于神经系统感染CHIKV和其他α病毒。