Inflammation and Hearing Loss Following Congenital CMV Infection

先天性巨细胞病毒感染后的炎症和听力损失

• 批准号: 10238050
• 负责人: William Jarvis Britt
• 金额: $ 61.8万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238050
• 关键词: Acute; Affect; Animal Model; Animals; Antiviral Agents; Auditory; Auditory system; Autopsy; Birth; Brazil; Cell physiology; Cells; Cellular Morphology; Cellular Tropism; Characteristics; Child; Child Health; Clinical; Clinical Trials; Cochlea; Cochlear nucleus; Cytomegalovirus; Cytomegalovirus Infections; Cytopathology; Development; Disease; Exhibits; Genetic; Goals; Hair Cells; Hearing; Hematogenous Spread; Herpesviridae; Human; Immune response; India; Infant; Infection; Infiltration; Inflammation; Inner Ear Infection; Investigation; Labyrinth; Lesion; Life; Link; Live Birth; Liver; Mediating; Mediator of activation protein; Modeling; Mononuclear; Morphology; Mus; Newborn Infant; Organ of Corti; Outcome; Pathway interactions; Patients; Pattern; Perinatal Infection; Peripheral; Reporting; Role; Route; Secondary to; Sensorineural Hearing Loss; Site; Specimen; Spleen; Structure; Therapeutic; Translating; Viral; Viremia; Virus; Virus Diseases; Virus Replication; adaptive immune response; clinical investigation; congenital cytomegalovirus; congenital infection; follow-up; hearing impairment; infant infection; insight; intraperitoneal; mouse model; neonatal infection; neuron loss; novel therapeutic intervention; perinatal period; prevent hearing loss; primary endpoint; progressive hearing loss; spiral ganglion; targeted treatment; virology

Abstract: Hearing loss associated with congenital human cytomegalovirus (HCMV) infection, a relatively frequent perinatal infection, accounts for nearly 25% of all causes of hearing loss in infants and children in the US. The mechanisms of disease caused by infection of the inner ear by this large herpesvirus are unknown, primarily because of hurdles inherent in the investigation of the inner ear in humans. We have developed an informative murine model of hearing loss in which newborn mice are infected peripherally and not intracranially with the closely related murine CMV. In this model, about 30-50% of infected mice develop sensorineural hearing loss and a significant number of mice with hearing loss exhibit progression in hearing loss, a clinically important feature of hearing loss in infants with HCMV associated hearing loss. Our findings strongly argue that virus-induced inflammation and not direct viral cytopathology is responsible for hearing loss and progressive hearing loss in this model. Our studies will explore this hypothesis by defining mechanisms of damage to the developing auditory system and hearing loss in animals associated with CMV-induced inflammation of the inner ear. Results from these studies will guide investigation into mechanisms of hearing loss in infants and children with HCMV associated hearing loss and identify therapeutic approaches that can be translated into treatment and prevention of hearing loss in CMV infected infants.

摘要： 先天性人巨细胞病毒（HCMV）感染相关的听力损失， 频繁的围产期感染，占婴儿听力损失所有原因的近25%， 美国的孩子。内耳感染引起的疾病的机制， 大疱疹病毒是未知的，主要是因为在调查中固有的障碍， 人类的内耳我们开发了一种信息丰富的听力损失小鼠模型，其中 新生小鼠外周感染而非颅内感染密切相关的鼠 巨细胞病毒在该模型中，约30-50%的感染小鼠发展为感音神经性听力损失， 相当数量的听力损失小鼠表现出听力损失的进展， HCMV相关性听力损失婴儿听力损失的重要特征。我们的研究结果 强烈认为病毒诱导的炎症而不是直接的病毒细胞病理学是负责的 听力损失和渐进性听力损失。我们的研究将探讨这一点 通过定义发育中的听觉系统和听力损伤的机制， 与CMV诱导的内耳炎症相关的动物损失。从这些 研究将指导对婴儿和儿童听力损失机制的调查， HCMV相关的听力损失，并确定治疗方法，可以转化为 CMV感染婴儿听力损失的治疗和预防。

项目成果

Cytomegalovirus Infection and Inflammation in Developing Brain.

• DOI: 10.3390/v13061078
• 发表时间: 2021-06-04
• 期刊: Viruses
• 作者: Krstanović F;Britt WJ;Jonjić S;Brizić I
• 通讯作者: Brizić I

NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection.

• DOI: 10.1084/jem.20201503
• 发表时间: 2021-05-03
• 期刊: The Journal of experimental medicine
• 作者: Kveštak D;Juranić Lisnić V;Lisnić B;Tomac J;Golemac M;Brizić I;Indenbirken D;Cokarić Brdovčak M;Bernardini G;Krstanović F;Rožmanić C;Grundhoff A;Krmpotić A;Britt WJ;Jonjić S
• 通讯作者: Jonjić S