Lethal H5N1 Virus Infection and Respiratory Disorders

致命的 H5N1 病毒感染和呼吸系统疾病

基本信息

批准号：
8561704
负责人：
Fadi Xu
金额：
$ 51.41万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8561704
关键词：
Abbreviations Address Adolescent Air Airway Resistance Animals Apoptosis Area Avian Influenza Biochemical Blood Pressure Blood gas Body Temperature Body Weight Brain Bronchoalveolar Lavage Fluid C Fiber Capsaicin Carotid Body Cell Nucleus Cessation of life Chronic Obstructive Airway Disease Data Dependency Depressed mood Development Disease Dyspnea Ensure Environmental air flow Fiber Functional disorder Ganglia Heart Rate Herpesvirus 1 Hong Kong Hypercapnia Hypoxemia Hypoxia Immunology Infection Influenza Influenza A Virus, H5N1 Subtype Invaded Knockout Mice Lesion Lung Measures Mediating Metabolism Mus Names Neuraxis Neurons Nodose Ganglion Nucleus solitarius Pathogenesis Pathology Pathway interactions Patients Peripheral Permeability Play Pneumonia Prevention strategy Pulmonary Diffusing Capacity Respiration Disorders Respiratory Failure Respiratory syncytial virus Role Saline Sensory Staging Structure of phrenic nerve Substance P Substance P Receptor Sudden infant death syndrome Symptoms Testing Travel Tyrosine 3-Monooxygenase Vaccines Vagus nerve structure Viral Viremia Virus Virus Diseases cigarette smoking density insight killings mortality mouse model neuronal cell body novel prevent public health relevance receptor expression relating to nervous system respiratory response substance P-saporin virology

项目摘要

DESCRIPTION (provided by applicant): Avian influenza A (H5N1) virus infection results in ~60% mortality in patients who present respiratory abnormalities from dyspnea and pulmonary inflammation during the first 6 days post-infection to respiratory failure with hypoxemia, leading to death several days later. The mechanisms underlying the respiratory failure responsible for the infection-induced death are unclear and no effective vaccine/treatment is available. Animal studies have focused on immunology and virology of the infection without studying respiratory pathophysiology. Additionally, these studies showed that upon pulmonary infection, the lethal H5N1 viruses, differing from nonlethal ones, initially invaded (2-3 days post-infection) the vagus nerve and then brain, resulting in death 8 days post-infection, pointing to a possible vagal involvement in H5N1 pathology. Pulmonary sensory fibers traveling within the vagus nerve are composed primarily of bronchopulmonary C-fibers (PCFs). Stimulation of PCFs peripherally triggers dyspnea and pulmonary inflammation and centrally induces depressed hypoxic and hypercapnic ventilatory responses (dHVR and dHCVR). These peripheral and central effects are achieved by PCFs releasing SP into the lungs and the middle region of the nucleus tractus solitarius (mNTS) to act on local neurokinin 1 receptor (NK1R), respectively. Because dHVR and dHCVR are responsible for generating respiratory failure, we recently tested these chemoreflexes at the early stage of the viral infection. Our preliminary data showed that HK483 (a lethal H5N1 strain) but not HK486 virus (a nonlethal one) led to remarkable dHVR and dHCVR 2-3 days post-infection without viremia and killed the mice 8 days post-infection. Interestingly, this death was absent in PCF-degenerated or SP-knockout mice. Therefore, in this project, we will first characterize the HK483 virus-induced cardiorespiratory disorders by measuring cardiorespiratory activities, pulmonary changes, and chemoreflexes in mice over the infection period and correlate the disorders to respiratory failure (death), thereby building a bas for further mechanistic studies. Second, we will define that HK483 virus invades PCFs to increase their activity and sensitivity and that PCF degeneration diminishes or prevents the virus-induced respiratory disorders (death). Third, we will reveal that HK483 virus promotes PCF-dependent SP release into the lungs and mNTS to upregulate NK1R expression in PCFs and mNTS neurons receiving PCF inputs. Moreover, the effects of systemic or peripheral blockade of NK1Rs and selective lesion of mNTS NK1R neurons on the HK483 virus-induced cardiorespiratory disorders and death will be determined. In this project, electrophysiological, biochemical, pharmacological, and immunocytochemical approaches will be used. Our predicted results as described above will: 1) form a novel neurovirological concept that lethal H5N1 virus invades PCFs to induce their morphological and functional changes; 2) gain new insight into the mechanisms underlying the pathogenesis of the lethal viral infection-induced respiratory failure; and 3) catalyze the development of preventive strategies and pharmacological therapies to protect against respiratory failure and death.

描述（由申请人提供）：甲型禽流感 (H5N1) 病毒感染导致约 60% 的患者死亡，这些患者在感染后的前 6 天内因呼吸困难和肺部炎症而出现呼吸异常，直至呼吸衰竭伴低氧血症，导致数人死亡几天后。导致感染引起死亡的呼吸衰竭的机制尚不清楚，并且没有有效的疫苗/治疗方法。动物研究侧重于感染的免疫学和病毒学，而不研究呼吸道病理生理学。此外，这些研究表明，肺部感染后，致命的 H5N1 病毒与非致命病毒不同，首先侵入（感染后 2-3 天）迷走神经，然后侵入大脑，导致感染后 8 天死亡，这表明H5N1 病理学可能涉及迷走神经。在迷走神经内传播的肺感觉纤维主要由支气管肺 C 纤维 (PCF) 组成。 PCF 的刺激在外周引发呼吸困难和肺部炎症，并在中枢诱导低氧和高碳酸血症通气反应（dHVR 和 dHCVR）。这些外周和中枢效应是通过 PCF 将 SP 释放到肺部和孤束核 (mNTS) 中部区域，分别作用于局部神经激肽 1 受体 (NK1R) 来实现的。由于 dHVR 和 dHCVR 会导致呼吸衰竭，因此我们最近在病毒感染的早期阶段测试了这些化学反射。我们的初步数据显示，HK483（一种致命的 H5N1 病毒株）而非 HK486 病毒（一种非致命病毒）在感染后 2-3 天产生显着的 dHVR 和 dHCVR，且没有病毒血症，并在感染后 8 天杀死小鼠。有趣的是，PCF 退化或 SP 敲除小鼠中不存在这种死亡。因此，在本项目中，我们将首先通过测量感染期间小鼠的心肺活动、肺部变化和化学反射来表征HK483病毒引起的心肺疾病，并将这些疾病与呼吸衰竭（死亡）相关联，从而为进一步研究奠定基础。机理研究。其次，我们将定义HK483病毒侵入PCF以增加其活性和敏感性，并且PCF变性减少或预防病毒引起的呼吸系统疾病（死亡）。第三，我们将揭示HK483病毒促进PCF依赖性SP释放到肺部和mNTS中，从而上调接受PCF输入的PCF和mNTS神经元中的NK1R表达。此外，还将确定NK1R的全身或外周阻断以及mNTS NK1R神经元的选择性损伤对HK483病毒诱导的心肺疾病和死亡的影响。在该项目中，将使用电生理学、生物化学、药理学和免疫细胞化学方法。我们的上述预测结果将：1）形成一个新的神经病毒学概念，即致命的H5N1病毒侵入PCF以诱导其形态和功能的变化； 2）对致命病毒感染引起的呼吸衰竭的发病机制有新的认识； 3) 促进预防策略和药物疗法的发展，以预防呼吸衰竭和死亡。