Lethal H5N1 Virus Infection and Respiratory Disorders

致命的 H5N1 病毒感染和呼吸系统疾病

• 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
• 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

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（由申请方提供）：禽流感A（H5 N1）病毒感染导致约60%的患者死亡，这些患者在感染后的前6天内出现呼吸困难和肺部炎症等呼吸异常，直至呼吸衰竭伴低氧血症，导致数天后死亡。呼吸衰竭导致感染性死亡的潜在机制尚不清楚，也没有有效的疫苗/治疗方法。动物研究集中在感染的免疫学和病毒学上，而没有研究呼吸道病理生理学。此外，这些研究表明，在肺部感染时，致命的H5 N1病毒，不同于非致命的，最初侵入（感染后2-3天）迷走神经，然后侵入脑，导致感染后8天死亡，这表明H5 N1病理学中可能涉及迷走神经。在迷走神经内行进的肺感觉纤维主要由支气管肺纤维C-纤维（PCF）组成。PCFs的刺激外周触发呼吸困难和肺部炎症，并中枢诱导抑制的低氧和高二氧化碳呼吸反应（dHVR和dHCVR）。这些外周和中枢效应是通过PCF将SP释放到肺和孤束核（mNTS）的中间区域以分别作用于局部神经激肽1受体（NK 1 R）来实现的。由于dHVR和dHCVR是导致呼吸衰竭的原因，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，HK 483（致死性H5 N1毒株）而不是HK 486病毒（非致死性毒株）在感染后2-3天导致显著的dHVR和dHCVR，而没有病毒血症，并在感染后8天杀死小鼠。有趣的是，这种死亡在PCF退化或SP敲除小鼠中不存在。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HK 483病毒诱导的心肺疾病，并将这些疾病与呼吸衰竭（死亡）相关联，从而为进一步的机制研究奠定基础。其次，我们将定义HK 483病毒侵入PCF以增加其活性和敏感性，PCF变性减少或预防病毒诱导的呼吸系统疾病（死亡）。第三，我们将揭示HK 483病毒促进PCF依赖性SP释放到肺和mNTS中，以上调PCF和接受PCF输入的mNTS神经元中的NK 1 R表达。此外，将确定全身或外周阻断NK 1 R和选择性损伤mNTS NK 1 R神经元对HK 483病毒诱导的心肺功能障碍和死亡的影响。在这个项目中，电生理学，生物化学，药理学和免疫细胞化学的方法将被使用。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H5 N1病毒侵入PCF，诱导其形态和功能的变化; 2）获得新的见解致命的病毒感染诱导的呼吸衰竭的发病机制;和3）促进预防策略和药物治疗的发展，以防止呼吸衰竭和死亡。