NEUROTROPIC CYTOMEGALOVIRUS DURING IMMUNOSUPPRESSION

巨细胞病毒（CMV）是一种重要的机会性病原体，估计在人群中的患病率为50-90%。虽然大多数免疫功能正常的个体不会发生临床感染，但免疫抑制的患者，如艾滋病患者或接受免疫抑制治疗的患者，可能会出现衰弱的神经功能障碍、精神障碍、认知障碍和潜在的致命感染。巨细胞病毒还可能进一步抑制免疫系统，并被认为是艾滋病痴呆综合征的一个辅助因素。缺乏适当的自然嗜神经巨细胞病毒感染动物模型限制了对病毒进入机制和在脑内传播的理解。该建议的中心假设是免疫抑制患者的系统性巨细胞病毒感染以可预测的局部模式通过特定机制传播到大脑，并受到宿主免疫疾病能力的强烈影响。下面的研究将定义系统性巨细胞病毒感染、宿主免疫和中枢神经系统疾病之间的关系。一种新的小鼠肠道外CMV接种导致嗜神经性CMV感染的模型将通过4种主要策略来验证这一假设：1)确定小鼠免疫缺陷的严重程度是否改变了对嗜神经性巨细胞病毒传播的易感性；2)确定巨细胞病毒感染中枢神经系统是否可以通过游离病毒、被感染的白细胞或直接通过轴突内转运到脑的血液传播发生；3)确定小鼠是否可以通过特异性免疫淋巴细胞群的过继转移来保护小鼠免受嗜神经性巨细胞病毒的感染。4)确定免疫或非特异性免疫T细胞的过继性转移是否可以减少或清除已建立的巨细胞病毒性脑炎。这一建议阐明了嗜神经巨细胞病毒作为一种主要的机会性中枢神经系统病原体的重要性，没有混杂变量，如合并HIV复制，并可能有助于推进巨细胞病毒相关脑炎和艾滋病痴呆综合征的诊断和治疗。本项目的培训将扩展、拓宽和深化我对传染病发病机制的了解，并培养我在免疫调节方面的智力和技术能力，这对我的科学独立性至关重要。培训将在耶鲁大学医学院进行，导师为神经外科教授Anthony van den Pol博士和高级神经科学家Nancy Ruddle博士，流行病学和公共卫生/免疫生物学和微生物疾病流行病学教授，世界级免疫学家，与Akiko Iwasaki博士合作。流行病学/公共卫生助理教授，在宿主对感染性微生物的免疫机制方面有很强的研究资历。

Cytomegalovirus (CMV) is an important opportunistic pathogen with an estimated prevalence in the human population of 50-90%. While most immunocompetent individuals do not develop clinical infection, immunosuppressed patients such as those with AIDS or undergoing immunosuppressive therapy open develop debilitating neurological deficits, mental disorders, cognitive impairment, and potentially fatal infection. CMV also may further suppress the immune system and has been suggested as a co-factor in AIDS dementia syndrome. Lack of an appropriate animal model of natural neurotropic CMV infection has limited understanding of virus entry mechanisms and dissemination in brain. The central hypothesis of this proposal is that systemic CMV infection in immunosuppressed patients disseminates to the brain through specific mechanisms in a predictable, localized pattern and is strongly influenced by the competency of host immune disease. The research described below will define the relationship of systemic CMV infection, host immunity and CNS disease. A novel murine model of parenteral CMV inoculation resulting in neurotropic CMV infection will be used to test this hypothesis through4 primary strategies: 1) determine whether severity of mouse immunodeficiency alters susceptibility to neurotropic CMV dissemination, 2) determine if CMV infection of the CNS can occur through hematogenous dissemination through free virus, infected leukocytes, or directly through intra-axonal transport to brain, 3) determine if mice are protected from neurotropic MCMV by adoptive transfer of specific immune lymphoid cell populations, 4.) determine whether adoptive transfer of immune or non-specific immune T cells can reduce or clear established CMV encephalitis. This proposal elucidates the significance of neurotropic CMV as a principal opportunistic CNS pathogen without confounding variables such as co-incident HIV replication and may help to advance the diagnosis and therapy of CMV related encephalitis and AIDS dementia syndrome. Training inherent to the proposal will extend, broaden, and deepen my knowledge of infectious disease pathogenesis and develop intellectual and technical competency in immune modulation crucial to my scientific independence. Training will be performed at Yale University School of Medicine under the mentorship of Anthony van den Pol, PhD, Professor of Neurosurgery, and a senior neuroscientist, Nancy Ruddle, PhD, Professor of Epidemiology and Public Health/Immunobiology and Epidemiology of Microbial Diseases, and world-class immunologist in collaboration with Akiko Iwasaki, PhD, Assistant Professor of Epidemiology/Public Health who has strong research credentials in the mechanism of host immunity to infectious microorganisms.