Modeling chikungunya virus neuroinvasion and neuropathogenesis in mice

项目总结 甲型病毒基孔肯雅病毒(Chikv)作为蚊子媒介，代表着重新出现的公共卫生问题。 扩散到新的领域。虽然CHIKV通常会导致关节炎，但高达16%的病例会导致 神经系统疾病，如脑炎和脑膜炎。幸存的患者通常会被留给长期的 神经缺陷，包括运动控制受损、情绪和行为去抑制以及认知 精神错乱。尽管发表了大量的临床病例和公共卫生影响报告，但人们对此知之甚少 CHIKV感染的神经发病机制。有限的可访问性和最低限度的再生性 中枢神经系统(CNS)为研究神经CHIKV的进程制造了不可逾越的障碍 在人类中感染，需要使用动物模型。小鼠已被广泛用于研究关节炎的形成。 CHIKV引起的疾病和其他甲型病毒引起的神经系统疾病，包括长期 神经后遗症。然而，几乎所有检测神经系统CHIKV感染的小鼠研究都利用了 新生或免疫低下的小鼠，不能准确反映神经发育或 易感人群的免疫状况。此外，无论是关节炎还是神经性疾病 甲型病毒引起的疾病已被证明主要是由免疫反应而不是 由于病毒本身，进一步有必要使用具有免疫能力的小鼠。我们小组的初步工作是 研究发现，虽然年轻成年C57BL/6J小鼠容易感染并复制中枢神经系统的病理 据报道，在人类颅内感染后，中枢神经系统感染不能在以下情况下持续实现 周边接种。相比之下，CC041小鼠，一个合作的交叉品系，持续地表现出感染 皮下接种后大脑和神经系统疾病的迹象，呈现出潜在的小鼠 评估CHIKV外周感染后所致神经系统疾病的模型。这项建议 目的研究CC041小鼠周围接种CHIKV后神经系统CHIKV感染的特征，并确定 CC041小鼠是否会患上人类所见的神经系统疾病和中枢神经系统病理。在目标1中，我们将 确定CHIKV感染CC041小鼠脑的机制和动力学。在目标2中，我们将 确定CC041小鼠是否出现类似于人类的中枢神经系统病理和长期神经后遗症 神经性CHIKV感染后的患者。我们的研究将建立一种新的神经发育- 合适的、具有免疫活性的外周CHIKV感染小鼠模型，为未来的深入研究奠定了基础 评估推动神经疾病发展的机制，并据此测试新的潜力 针对CHIKV和其他甲型病毒神经系统感染的疫苗、抗病毒药物和宿主导向治疗。

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.