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.

抽象的： 与先天性人类巨细胞病毒（HCMV）感染相关的听力损失是一种相对 频繁的围产期感染，占婴儿听力损失所有原因的近 25%， 在美国的孩子们。内耳感染引起疾病的机制 大型疱疹病毒尚不清楚，主要是因为研究中固有的障碍 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 新生小鼠受到外周感染，而不是与密切相关的小鼠颅内感染 巨细胞病毒。在这个模型中，大约 30-50% 的受感染小鼠出现感音神经性听力损失和 大量患有听力损失的小鼠表现出听力损失的进展，这是一项临床研究 HCMV 相关性听力损失婴儿听力损失的重要特征。我们的发现 强烈认为是病毒引起的炎症而不是直接的病毒细胞病理学造成的 对于该模型中的听力损失和进行性听力损失。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受损的机制来提出假设 动物的损失与 CMV 引起的内耳炎症有关。这些结果 研究将指导婴儿和儿童听力损失机制的调查 HCMV 与听力损失相关并确定可转化为的治疗方法 治疗和预防巨细胞病毒感染婴儿听力损失。

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