Respiratory syncytial virus (RSV) is the most important respiratory pathogen in infancy and early childhood and is associated with the development of long-term airway inflammation and hyperreactivity whose mechanisms remain unclear. Our recent research (HL-61007) has shown that RSV makes rat airways abnormally susceptible to neurogenic inflammation through mechanisms involving the increased expression of nerve growth factor (NGF) and its trkA and p75 receptors, and we have confirmed overexpression of neurotrophic factors [NGF and brain-derived neurotrophic factors (BDNF)] and trkA receptors in the lower airways of human infants with RSV bronchiolitis. We also found that the recruitment of lymphocytes and monocytes to infected airways is amplified by concomitant stimulation of substance P (SP)-containing sensory afferents and that RSV induces maturation of large numbers of mast cells in close juxtaposition with these nerve fibers, whose activation triggers the synthesis/release of leukotrienes in the airways. Furthermore, our studies indicate that the potentiation of neurogenic inflammation persists long after resolution of the acute RSV infection and that neurogenic responses to RSV in young rats are qualitatively and quantitatively different from adult rats. Starting from these observations, we now hypothesize that dysregulation of the expression of neurotrophins [NGF, BDNF, and neurotrophins (NT) 3 and 4) and their receptors (trkA/B/C and p75) in developing airways by early-life RSV infection leads to remodeling of the sensorineural network in the respiratory tract and to development of complex neuro-immune interactions that amplify and protract airway inflammation and hyperreactivity. We also hypothesize, based on preliminary data, that exposure to hyperoxia in the neonatal period modifies the effect of the virus on the expression of neurotrophic factors and receptors. Finally, we hypothesize that RSV-induced changes in neurotrophin expression are responsible for the aberrant responses of cellular effectors of inflammation and allergy to the stimulation of sensory nerves. The following specific aims are organized around the evaluation of these hypotheses: 1) To study the changes in expression and localization of neurotrophins and neurotrophin receptors in the lungs resulting from early-life RSV infection, and correlate these changes to neurogenic inflammation;2) To determine the role of neurotrophins and neurotrophin receptors in the recruitment and activation of lymphocytes and monocytes into the respiratory tract infected with RSV;and 3) To analyze the role of neurotrophins and neurotrophin receptors in the differentiation of mast cells and modulation of the leukotriene pathway in the respiratory tract infected with RSV. These studies will provide new important information concerning neuro-immune interactions in RSV-infected airways and on the pathogenesis of post-RSV childhood asthma, and may lead to new therapeutic and prophylactic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL061007-10
Application #
8503634
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Noel, Patricia
Project Start
1999-07-01
Project End
2017-04-30
Budget Start
2012-07-18
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$393,100
Indirect Cost
$146,775
Name
Cleveland Clinic Lerner
Department
Pediatrics
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Brown, Paul M; Harford, Terri J; Agrawal, Vandana et al. (2017) Prenatal Exposure to Respiratory Syncytial Virus Alters Postnatal Immunity and Airway Smooth Muscle Contractility during Early-Life Reinfections. PLoS One 12:e0168786
Chakraborty, Sreeparna; Castranova, Vincent; Perez, Miriam K et al. (2017) Nanoparticles-induced apoptosis of human airway epithelium is mediated by proNGF/p75NTR signaling. J Toxicol Environ Health A 80:53-68
Rezaee, Fariba; Linfield, Debra T; Harford, Terri J et al. (2017) Ongoing developments in RSV prophylaxis: a clinician's analysis. Curr Opin Virol 24:70-78
Foster, Charles B; Coelho, Ritika; Brown, Paul M et al. (2017) A comparison of hospitalized children with enterovirus D68 to those with rhinovirus. Pediatr Pulmonol 52:827-832
Rezaee, Fariba; Harford, Terri J; Linfield, Debra T et al. (2017) cAMP-dependent activation of protein kinase A attenuates respiratory syncytial virus-induced human airway epithelial barrier disruption. PLoS One 12:e0181876
Manti, Sara; Cuppari, Caterina; Lanzafame, Angela et al. (2017) Detection of respiratory syncytial virus (RSV) at birth in a newborn with respiratory distress. Pediatr Pulmonol 52:E81-E84
Griffiths, Pamela S; Walton, Cheryl; Samsell, Lennie et al. (2016) Maternal high-fat hypercaloric diet during pregnancy results in persistent metabolic and respiratory abnormalities in offspring. Pediatr Res 79:278-86
Anfuso, Antony; Ramadan, Hassan; Terrell, Andrew et al. (2015) Sinus and adenoid inflammation in children with chronic rhinosinusitis and asthma. Ann Allergy Asthma Immunol 114:103-10
Brown, Paul M; Schneeberger, Dana L; Piedimonte, Giovanni (2015) Biomarkers of respiratory syncytial virus (RSV) infection: specific neutrophil and cytokine levels provide increased accuracy in predicting disease severity. Paediatr Respir Rev 16:232-40
Piedimonte, Giovanni; Perez, Miriam K (2014) Alternative mechanisms for respiratory syncytial virus (RSV) infection and persistence: could RSV be transmitted through the placenta and persist into developing fetal lungs? Curr Opin Pharmacol 16:82-8

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