Respiratory virus infections modulate the sensory nervous system leading to sneezing, sore throat, coughing, reflex secretions and wheezing. For many this is a self-limiting problem;for others this can progress to significant morbidity. In fac, viral infections are the leading cause of asthma exacerbations in children, and are also a common cause of COPD exacerbation. Viral infections are also thought to be a leading cause of chronic unproductive cough that is said to affect as many as 10% of the population. The long-range goal of this proposal is to develop at a better understanding of the mechanisms and mediators involved in respiratory virus-induced sensory neuromodulation.
In Aim 1 we specifically address on our hypothesis, supported by preliminary data, that viral infection leads to a phenotypic change in the vagal extrapulmonary A? fibers such they take on a C-fiber nociceptor-like phenotype. We focus on the nodose extrapulmonary A-fibers because they terminate just beneath the epithelium in large airways (the target cell in many respiratory virus infections) and because when they are activated it leads to coughing, reflex secretions and bronchoconstriction. We hypothesize that viral infections induce, de novo, the expression of the ligand-gated ion channels TRPV1, TRPA1, and purinergic receptors, in the A-fiber neurons rendering them responsive to myriad stimuli they would ordinarily be unresponsive to. We address this hypothesis at the level of gene expression in single identified neurons.
In Aim 2 we further address this hypothesis at a functional level both electrophysiologically by recording action potential discharge from single A? nerve terminals in the trachea, and physiologically using the cough reflex as an outcome.
In Aims 3 -4 experiments are designed to address the hypothesis that the mechanisms underlying the viral-induced neuroplasticity involved brain-derived neurotrophic factor (BDNF/NT3) and/or glial cell-derived neurotrophic factor ligands (GFLs) interacting with the TRKB and GFR? receptors, respectively. We address our hypotheses using a strategy of mimicry, pharmacological antagonism and by making use of our recently validated method to silence gene expression in vagal sensory neurons in vivo with adeno-associated virus-sh-RNAs delivered to the nodose ganglion. The results from our multidisciplinary approach should be of intrinsic value in providing new knowledge regarding sensory neuroplasticity in the airways. The results will also shed new light on the complex pathophysiology of respiratory viral infections and possibly suggest new therapeutic strategies for treatment aimed at limiting viral evoked exacerbations of asthma, COPD, and chronic cough.

Public Health Relevance

Respiratory viruses modulate sensory nerves in the airways leading to sneezing, sore throat, nonproductive coughing, increases mucus secretion, and reversible bronchospasm. They are a leading cause of asthma attacks, chronic cough and COPD exacerbations. The long-range goal of this proposal is to develop a better understanding the mechanisms and mediators involved in viral infection-induced sensory neuromodulation in the respiratory tract.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL112919-02
Application #
8701369
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Noel, Patricia
Project Start
2013-07-15
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Han, Liang; Limjunyawong, Nathachit; Ru, Fei et al. (2018) Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness. Nat Neurosci 21:324-328
Zaccone, Eric J; Lieu, TinaMarie; Muroi, Yukiko et al. (2016) Parainfluenza 3-Induced Cough Hypersensitivity in the Guinea Pig Airways. PLoS One 11:e0155526
Zaccone, Eric J; Undem, Bradley J (2016) Airway Vagal Neuroplasticity Associated with Respiratory Viral Infections. Lung 194:25-9
McAlexander, M Allen; Gavett, Stephen H; Kollarik, Marian et al. (2015) Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse. Respir Physiol Neurobiol 212-214:20-4
Undem, Bradley J; Zaccone, Eric; McGarvey, Lorcan et al. (2015) Neural dysfunction following respiratory viral infection as a cause of chronic cough hypersensitivity. Pulm Pharmacol Ther 33:52-6
Dicpinigaitis, P V; Morice, A H; Birring, S S et al. (2014) Antitussive drugs--past, present, and future. Pharmacol Rev 66:468-512