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

• 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
• 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

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 甲病毒基孔肯雅病毒（CHIKV）作为蚊子媒介， 蔓延到新的领域。虽然CHIKV通常诱导致关节炎性疾病，但高达16%的病例导致 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 神经缺陷，包括运动控制受损，情绪和行为抑制解除，以及认知功能障碍， 紊乱尽管有许多已发表的临床病例和公共卫生影响报告， CHIKV感染的神经发病机制。有限的可及性和最低限度的再生性质， 中枢神经系统（CNS）对研究神经系统CHIKV的过程造成了不可逾越的障碍 感染人类，需要使用动物模型。小鼠已被广泛用于研究关节炎 由CHIKV诱导的疾病和由其他甲病毒诱导的神经系统疾病，包括长期 神经后遗症然而，几乎所有检查神经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 易感人群的免疫状态。此外，无论是关节炎和神经 甲病毒诱导的疾病已显示主要由免疫应答介导， 病毒本身，进一步需要使用免疫活性小鼠。我们小组的前期工作 发现年轻的成年C57 BL/6 J小鼠易受感染并复制CNS病理 在颅内感染后的人类中报告，CNS感染在以下情况下不能一致地实现 外周接种相比之下，CC 041小鼠（协作交叉品系）始终表现出感染 皮下接种后出现脑的损伤和神经系统疾病的体征， 模型，通过该模型评估外周感染后由CHIKV诱导的神经疾病。这项建议 目的是表征外周接种后CC 041小鼠中的神经CHIKV感染，并确定 CC 041小鼠是否发生在人类中观察到的神经系统疾病和CNS病理。在目标1中，我们 确定CHIKV感染CC 041小鼠脑的机制和动力学。在目标2中，我们将 确定CC 041小鼠是否发生与人类相似的CNS病理学和长期神经学后遗症 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、具有免疫能力的外周CHIKV感染小鼠模型，为未来的深入研究奠定基础 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 疫苗、抗病毒药和针对CHIKV和其他甲病毒的神经感染的宿主定向治疗。