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: 9088505
• 负责人: Fadi Xu
• 金额: $ 54万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088505
• 关键词: Abbreviations; Address; Adolescent; Airway Resistance; Animals; Apoptosis; Area; Avian Influenza; Biochemical; Blood gas; Brain; C Fiber; Cells; Cessation of life; Data; Dependency; Depressed mood; Development; Disease; Dyspnea; Electrophysiology (science); Ensure; Fiber; Functional disorder; Health; Herpesvirus 1; Hypercapnia; Hypoxemia; Hypoxia; Immunology; Infection; Influenza A Virus, H5N1 Subtype; Influenza A virus; Invaded; Knockout Mice; Lesion; Lung; Measures; Mediating; Metabolism; Mus; Names; Neurons; Nucleus solitarius; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Permeability; Play; Prevention strategy; Pulmonary Diffusing Capacity; Pulmonary Inflammation; Respiration Disorders; Respiratory Failure; Respiratory Signs and Symptoms; Role; Saline; Sensory; Staging; Structure of phrenic nerve; Substance P Receptor; Testing; Travel; Vaccines; Vagus nerve structure; Viremia; Virus; Virus Diseases; Virus Replication; density; insight; killings; mortality; mouse model; novel; prevent; receptor expression; relating to nervous system; respiratory; response; 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（由申请人提供）：禽流感（H5N1）病毒感染导致〜60％的死亡率，患者在感染后6天对呼吸困难和肺部炎症引起的呼吸异常和低氧血症呼吸道衰竭的呼吸异常，几天后导致死亡。导致感染引起的死亡的呼吸衰竭背后的机制尚不清楚，没有有效的疫苗/治疗。动物研究的重点是感染的免疫学和病毒学，而无需研究呼吸病理生理学。此外，这些研究表明，在肺部感染后，致命的H5N1病毒与非致死性的病毒不同，最初被侵入（感染后2-3天）神经神经，然后大脑，导致感染后8天死亡，指向H5N1病理学中可能的迷传。在迷走神经内行进的肺感觉纤维主要由支气管肺C纤维（PCF）组成。 PCF的刺激在外围刺激会触发呼吸困难和肺部炎症，并集中诱导低氧和过度易通气反应（DHVR和DHCVR）。这些外围和中心效应是通过将SP释放到肺部和核心核的中部区域（MNT）的PCF来实现的，分别作用于局部神经蛋白1受体（NK1R）。由于DHVR和DHCVR负责产生呼吸衰竭，因此我们最近在病毒感染的早期测试了这些化学反射。我们的初步数据表明，HK483（致命的H5N1菌株），但没有HK486病毒（一种非致死性）导致感染后2-3天引起了显着的DHVR和DHCVR，而没有病毒性，并在感染后8天杀死了小鼠。有趣的是，PCF脱生或SP-KNOCKOUT小鼠没有这种死亡。因此，在该项目中，我们将首先通过测量感染期间小鼠的心肺活性，肺部变化和化学反射剂来表征HK483病毒诱导的心肺疾病，并将疾病与呼吸衰竭（死亡）相关联（死亡），从而为进一步的机械研究而建立基础。其次，我们将定义HK483病毒侵入PCF以提高其活性和敏感性，并且PCF变性会减少或阻止病毒诱导的呼吸系统疾病（死亡）。第三，我们将揭示HK483病毒可促进依赖PCF的SP释放到肺和MNT中，以上调接收PCF输入的PCF和MNTS神经元中的NK1R表达。此外，将确定NK1RS的全身性或周围阻塞以及MNTS NK1R神经元对HK483病毒诱导的心肺疾病和死亡的选择性病变的影响。在这个项目中，将使用电生理，生化，药理学和免疫细胞化学方法。如上所述，我们的预测结果将：1）形成一种新型的神经病毒学概念，即致命的H5N1病毒侵入PCF以诱导其形态和功能变化； 2）对致命病毒感染引起的呼吸衰竭的发病机理的基础机制有了新的了解； 3）催化预防策略和药理疗法的发展，以防止呼吸衰竭和死亡。

项目成果

Roles of Bronchopulmonary C-fibers in airway Hyperresponsiveness and airway remodeling induced by house dust mite.

• DOI: 10.1186/s12931-017-0677-8
• 发表时间: 2017-11-29
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Yang Z;Zhuang J;Zhao L;Gao X;Luo Z;Liu E;Xu F;Fu Z
• 通讯作者: Fu Z

Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilatory response in mice.

• DOI: 10.1152/ajplung.00324.2018
• 发表时间: 2019-03
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Jianguo Zhuang;N. Zang;Chunyan Ye;Fadi Xu

Intralaryngeal application of ATP evokes apneic response mainly via acting on P2X3 (P2X2/3) receptors of the superior laryngeal nerve in postnatal rats.

喉内应用 ATP 主要通过作用于出生后大鼠喉上神经的 P2X3 (P2X2/3) 受体引起呼吸暂停反应。

• DOI: 10.1152/japplphysiol.00091.2021
• 发表时间: 2021
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Zhuang,Jianguo;Gao,Xiuping;Wei,Wan;Pelleg,Amir;Xu,Fadi
• 通讯作者: Xu,Fadi

Liquiritin apioside attenuates laryngeal chemoreflex but not mechanoreflex in rat pups.

甘草苷芹菜苷可减弱大鼠幼仔的喉部化学反射，但不会减弱机械感受反射。

• DOI: 10.1152/ajplung.00306.2019
• 发表时间: 2020
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Wei,Wan;Gao,Xiuping;Zhao,Lei;Zhuang,Jianguo;Jiao,Yang;Xu,Fadi
• 通讯作者: Xu,Fadi

Resveratrol suppresses persistent airway inflammation and hyperresponsivess might partially via nerve growth factor in respiratory syncytial virus-infected mice.

• DOI: 10.1016/j.intimp.2015.05.031
• 发表时间: 2015-09
• 期刊: International immunopharmacology
• 影响因子: 5.6
• 作者: N. Zang;Simin Li;Wei Li;Xiao-hong Xie;L. Ren;X. Long;Jun Xie;Yu Deng;Z. Fu;Fadi Xu