Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
Elife. 2022 May 5;11:e74462. doi: 10.7554/eLife.74462.
Central nervous system (CNS) infections are a major cause of human morbidity and mortality worldwide. Even patients that survive, CNS infections can have lasting neurological dysfunction resulting from immune and pathogen induced pathology. Developing approaches to noninvasively track pathology and immunity in the infected CNS is crucial for patient management and development of new therapeutics. Here, we develop novel MRI-based approaches to monitor virus-specific CD8+ T cells and their relationship to cerebrovascular pathology in the living brain. We studied a relevant murine model in which a neurotropic virus (vesicular stomatitis virus) was introduced intranasally and then entered the brain via olfactory sensory neurons - a route exploited by many pathogens in humans. Using T2*-weighted high-resolution MRI, we identified small cerebral microbleeds as an early form of pathology associated with viral entry into the brain. Mechanistically, these microbleeds occurred in the absence of peripheral immune cells and were associated with infection of vascular endothelial cells. We monitored the adaptive response to this infection by developing methods to iron label and track individual virus specific CD8+ T cells by MRI. Transferred antiviral T cells were detected in the brain within a day of infection and were able to reduce cerebral microbleeds. These data demonstrate the utility of MRI in detecting the earliest pathological events in the virally infected CNS as well as the therapeutic potential of antiviral T cells in mitigating this pathology.
中枢神经系统 (CNS) 感染是全球范围内导致人类发病率和死亡率的主要原因。即使患者存活下来，CNS 感染也会因免疫和病原体引起的病理而导致持久的神经功能障碍。开发非侵入性方法来跟踪感染 CNS 中的病理和免疫对于患者管理和新疗法的开发至关重要。在这里，我们开发了新的基于 MRI 的方法来监测病毒特异性 CD8+ T 细胞及其与受感染大脑中的脑血管病理的关系。我们研究了一个相关的小鼠模型，其中神经嗜性病毒（水疱性口炎病毒）通过鼻腔内引入，然后通过嗅觉感觉神经元进入大脑 - 这是许多人类病原体利用的途径。使用 T2*-加权高分辨率 MRI，我们确定了小的脑微出血作为与病毒进入大脑相关的早期病理形式。从机制上讲，这些微出血发生在没有外周免疫细胞的情况下，并且与血管内皮细胞的感染有关。我们通过开发通过 MRI 对单个病毒特异性 CD8+ T 细胞进行铁标记和跟踪的方法来监测对这种感染的适应性反应。转移的抗病毒 T 细胞在感染后一天内即可在大脑中检测到，并能够减少脑微出血。这些数据表明 MRI 在检测病毒感染 CNS 中最早的病理事件以及抗病毒 T 细胞在减轻这种病理方面的治疗潜力方面的实用性。
