MCMV Infection of the Developing CNS: Neuroinvasion and Immune Control

发育中的中枢神经系统的 MCMV 感染：神经侵袭和免疫控制

• 批准号: 8039217
• 负责人: William Jarvis Britt
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039217
• 关键词: Adult; Animal Model; Animal Viruses; Animals; Antiviral Therapy; Biological Models; Birth; Brain; Brain Diseases; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Central Nervous System Infections; Characteristics; Child; Cytomegalovirus; Cytomegalovirus Infections; Development; Disease; Dose; Encephalitis; Endothelium; Exhibits; Fetus; Generations; Genes; Genetic Transcription; Goals; Growth; Hepatic; Human; Immune; Immune response; Immunity; Immunocompromised Host; Infant; Infection; Infiltration; Inflammation; Interferons; Investigation; Lead; Maintenance; Microglia; Modeling; Morbidity - disease rate; Mothers; Murid herpesvirus 1; Mus; Natural History; Natural Immunity; Nature; Nervous System Trauma; Neuraxis; Neuroglia; Neurologic; Neurons; Newborn Animals; Newborn Infant; Outcome; Pathogenesis; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Physiological; Prevention; Resolution; Role; Route; Sensorineural Hearing Loss; Specimen; T-Lymphocyte; Therapeutic; Tissues; Transcript; Translating; Vaccine Design; Vaccines; Viral; Viremia; Virus; Virus Diseases; Virus Replication; adaptive immunity; cell type; hearing impairment; macrophage; monocyte; mouse model; neutralizing antibody; novel strategies; peripheral blood; public health relevance; response

DESCRIPTION (provided by applicant): Congenital human cytomegalovirus (HCMV) infection represents an important cause of neurological damage in children and is the leading cause of non-familial hearing loss in the US. Little is understood about the pathogenesis of this infection because suitable models of central nervous system (CNS) infection are lacking. We have developed a murine model of congenital HCMV infection which recapitulates many of the histopathological and neurodevelopmental abnormalities described in congenital HCMV infections, including hearing loss in surviving mice. In contrast to earlier models, newborn mice injected peripherally with murine CMV develop viremia and subsequently, encephalitis. Because newborn mice are neurodevelopmentally and immunologically equivalent to late 2nd trimester human fetuses, this model has also enabled us to study resolution of this virus infection in a developing animal. In this proposal we will study aspects of the CNS infection in these animals including mechanisms of neuroinvasion, the contribution of innate immune responses in clearance of the virus from the CNS, and the interplay between innate immunity and adaptive immune responses in clearance of virus from the CNS. Lastly, the contribution of both innate and adaptive immunity in persistent CNS infection in adult mice infected as newborns will be studied. We anticipate that parameters of the pathogenesis of CMV infection in the developing CNS will be identified from these studies. Furthermore, we believe that these findings can be translated directly into more focused studies in humans that could lead to new approaches for prevention and treatment of this important infection. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus infection in the developing fetus is a major cause of brain disease in infants and children. Currently no vaccines or treatment exist for this infection that is transmitted from the mother to the fetus. This project will utilize a highly related mouse virus and a mouse model of this disease to understand the characteristics of this infection that result in brain infection and the immune responses that limit virus growth and damage to the developing brain.

描述(由申请人提供)：先天性人类巨细胞病毒(HCMV)感染是导致儿童神经损伤的重要原因，也是美国非家族性听力损失的主要原因。由于缺乏合适的中枢神经系统(CNS)感染模型，对这种感染的发病机制知之甚少。我们已经建立了一种先天性HCMV感染的小鼠模型，它概括了先天性HCMV感染所描述的许多组织病理学和神经发育异常，包括存活小鼠的听力损失。与早期模型不同的是，外周注射小鼠巨细胞病毒的新生小鼠会出现病毒血症，随后会出现脑炎。由于新生的小鼠在神经发育和免疫学上与妊娠晚期的人类胎儿相同，这个模型也使我们能够研究这种病毒感染在发育中的动物中的分解。在这个方案中，我们将研究这些动物的中枢神经系统感染的一些方面，包括神经侵袭的机制，先天免疫反应在清除病毒从中枢神经系统中的作用，以及先天免疫和获得性免疫反应之间的相互作用。最后，我们将研究先天免疫和获得性免疫在新生感染成年小鼠持续中枢神经系统感染中的作用。我们预计CMV感染在发育中的中枢神经系统的发病机制参数将从这些研究中确定。此外，我们认为，这些发现可以直接转化为对人类的更有针对性的研究，从而可能导致预防和治疗这种重要感染的新方法。 公共卫生相关性：发育中胎儿中的人类巨细胞病毒感染是婴儿和儿童脑部疾病的主要原因。目前还没有针对这种从母亲传染给胎儿的感染的疫苗或治疗方法。该项目将利用高度相关的小鼠病毒和这种疾病的小鼠模型来了解导致脑感染的这种感染的特征，以及限制病毒生长和对发育中大脑损害的免疫反应。