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.
Avian influenza A (H5N1) virus is fatal to patients as a result of ensuring respiratory failure, but the pathogenesis of the respiratory failure remains unknown. This project will focus on establishing a mouse model infected by lethal H5N1 virus that presents the major respiratory symptoms clinically observed and will further elucidate the underlying mechanisms. The studies will gain insight into the respiratory pathophysiology of the lethality induced by the infection, and most importantly, highlight new targets for preventing and therapeutically intervening in the respiratory failure in these patients.
|Yang, Zhimei; Zhuang, Jianguo; Zhao, Lei et al. (2017) Roles of Bronchopulmonary C-fibers in airway Hyperresponsiveness and airway remodeling induced by house dust mite. Respir Res 18:199|
|Zhuang, Jianguo; Gao, Xiuping; Gao, Franklin et al. (2017) Mu-opioid receptors in the caudomedial NTS are critical for respiratory responses to stimulation of bronchopulmonary C-fibers and carotid body in conscious rats. Respir Physiol Neurobiol 235:71-78|
|Gao, Xiuping; Zhao, Lei; Zhuang, Jianguo et al. (2017) Prenatal nicotinic exposure prolongs superior laryngeal C-fiber-mediated apnea and bradycardia through enhancing neuronal TRPV1 expression and excitation. FASEB J 31:4325-4334|
|Zhao, Lei; Zhuang, Jianguo; Zang, Na et al. (2016) Prenatal nicotinic exposure upregulates pulmonary C-fiber NK1R expression to prolong pulmonary C-fiber-mediated apneic response. Toxicol Appl Pharmacol 290:107-15|
|Zhuang, Jianguo; Gao, Peng; Pollock, Zemmie et al. (2016) Depressed Hypoxic and Hypercapnic Ventilatory Responses at Early Stage of Lethal Avian Influenza A Virus Infection in Mice. PLoS One 11:e0147522|
|Zang, Na; Zhuang, Jianguo; Deng, Yu et al. (2016) Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection. J Virol 90:2536-43|
|Zang, Na; Li, Simin; Li, Wei et al. (2015) Resveratrol suppresses persistent airway inflammation and hyperresponsivess might partially via nerve growth factor in respiratory syncytial virus-infected mice. Int Immunopharmacol 28:121-8|