Sequelae of Lassa Fever

拉沙热的后遗症

基本信息

批准号：
10326863
负责人：
Slobodan Paessler
金额：
$ 72.73万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-09 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326863
关键词：
Acoustic Nerve Acute Address Adoptive Transfer Affect Africa Animal Model Animals Annual Reports Auditory Behavior CD3 Antigens Case Study Clinical Containment Convalescence Data Development Disease Etiology Exhibits Future Goals Health system Hemorrhage Home Hospitals Human Immune Immunologics Immunology Individual Infection Injury Interferon-alpha Labyrinth Lassa Fever Lassa virus Literature Location Measures Mediating Medical Modeling Molecular Virology Mus Neuraxis Neurologic Neurons Neurosciences Newborn Infant Nigeria Pathogenesis Pathologic Patients Phase Physiological Plant Roots Prevalence Process Public Health Quality of life Research Rodent Model Role Routine Diagnostic Tests Sensory Sudden Hearing Loss Survivors Symptoms Systemic infection T cell response T-Cell Depletion T-Lymphocyte TNFSF6 gene Techniques Time Tissues United States Viral Antigens Virus Diseases auditory pathway base clinical diagnostics experimental study functional disability gain of function hearing impairment hearing screening mortality mouse model noninvasive diagnosis novel perforin prevent recruit tool

项目摘要

PROJECT SUMMARY Hearing loss is one of the most prevalent sensory deficits that affect one in five individuals in the United States. While the underlying etiology can vary widely, viral infections are speculated to be associated with hearing loss with a sudden onset. Lassa fever (LF), caused by Lassa virus (LASV), is a major public health threat in West Africa and is characterized by acute hemorrhagic disease and/or neurological sequelae, and up to 500,000 cases are reported annually. Approximately 30% of LF survivors develop sudden onset hearing loss weeks or months after leaving the hospital, placing a huge burden on the public health system and impacting patients' quality of life. This phenomenon is quite unique because it typically develops at later stages of the disease process, thus making LF the only viral infection described in medical literature that induces hearing loss mostly in the convalescence phase. Until now, the lack of a robust animal model exhibiting sudden onset hearing loss induced by LASV prevented the mechanistic study of this clinical feature. To address this need, we developed a novel murine model for LF that mimics many symptoms of human LF. Most importantly, our model consistently reproduced the hearing loss in animals that were recovering from infection. This powerful tool will allow us, for the first time, to study the pathogenesis of hearing loss associated with LF, in a maximum containment BSL-4 setting. The long-term goal of our research is to identify the immunological and pathological mechanisms responsible for LASV-induced hearing loss in human patients to enable future treatment. The objective of this application is to use our physiologically relevant LF mouse model to study the mechanism of LF associated hearing loss, as well as to assess auditory damage of LF survivors in West Africa. Therefore, we propose the following Specific Aims: 1. Determine the mechanism of hearing loss in LASV-infected Stat1-/- mice. We will investigate the underlying mechanism by focusing on the inner ear, as well as determining the involvement of the central nervous system in hearing loss, by studying the auditory behavior of infected mice in order to define the localization of the injury and assess histopathological changes in the inner ear. 2. Identify the role of T cells in the development of hearing loss by performing loss/gain of function experiments. We will utilize T cell depletion and adoptive transfer techniques to determine the contribution of T cells to hearing loss in infected Stat1-/- mice. We will also identify the viral antigen most essential for T cell recruitment to the auditory nerve. 3. Determine the degree of hearing loss and location of functional damage in human patients exhibiting SHL after surviving LASV infection. We propose to investigate the underlying the hearing loss in documented LF survivors in Nigeria by using noninvasive diagnostic tests routinely performed during newborn hearing screening in the USA.

项目概要听力损失是最普遍的感觉缺陷之一，影响着美国五分之一的人。虽然潜在的病因可能有很大差异，但病毒感染据推测与听力损失有关突然发作。拉沙热（LF）由拉沙病毒（LASV）引起，是西方国家的主要公共卫生威胁非洲，以急性出血性疾病和/或神经系统后遗症为特征，多达 500,000 每年都会报告病例。大约 30% 的 LF 幸存者会在数周或数周内突然出现听力损失出院几个月后，给公共卫生系统带来巨大负担并影响患者的健康生活质量。这种现象非常独特，因为它通常发生在疾病的后期阶段过程，从而使 LF 成为医学文献中描述的唯一主要导致听力损失的病毒感染处于恢复期。到目前为止，缺乏表现出突发性听力损失的稳健动物模型 LASV 诱发的病毒阻碍了这一临床特征的机制研究。为了满足这一需求，我们开发了一种新颖的 LF 小鼠模型，模仿人类 LF 的许多症状。最重要的是，我们的模型一致地再现了从感染中恢复的动物的听力损失。这个强大的工具将让我们第一次能够最大程度地研究与 LF 相关的听力损失的发病机制收容 BSL-4 设置。我们研究的长期目标是确定造成这种情况的免疫学和病理学机制用于 LASV 引起的人类患者听力损失，以便将来进行治疗。该应用程序的目标是使用我们的生理相关 LF 小鼠模型来研究 LF 相关听力损失的机制，如以及评估西非 LF 幸存者的听觉损伤。因此，我们提出以下建议具体目标： 1. 确定 LASV 感染的 Stat1-/- 小鼠听力损失的机制。我们将调查通过关注内耳以及确定中枢的参与来了解潜在的机制通过研究受感染小鼠的听觉行为来确定听力损失中的神经系统损伤定位并评估内耳的组织病理学变化。 2. 确定 T 细胞在通过进行功能丧失/增强实验来了解听力损失的发展。我们将利用 T 细胞耗竭以及过继转移技术，以确定 T 细胞对受感染 Stat1-/- 听力损失的影响老鼠。我们还将鉴定对于 T 细胞募集到听觉神经最重要的病毒抗原。 3. 确定患有 SHL 的人类患者听力损失的程度和功能损伤的位置幸存 LASV 感染。我们建议调查记录的 LF 中潜在的听力损失尼日利亚的幸存者通过使用新生儿听力期间常规进行的无创诊断测试在美国进行筛选。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

COVID-19 Subclinical Infection and Immunity: A Review.

DOI：
10.4103/njm.njm_85_21
发表时间：
2021-11
期刊：
Nigerian journal of medicine : journal of the National Association of Resident Doctors of Nigeria
影响因子：
0
作者：
Bartekwa JW;Abene EE;Luka PD;Yilgwan CS;Shehu NY
通讯作者：
Shehu NY

Lassa fever-induced sensorineural hearing loss: A neglected public health and social burden.