Respiratory syncytial virus (RSV) is the most important respiratory pathogen in infancy and early childhood, and strong epidemiologic evidence links this infection with subsequent wheezing and asthma. In the previous funding cycle, we found that RSV is able to spread hematogenously across the placenta from the respiratory tract of rat dams to their offspring. Prenatal RSV infection is associated with increased airway reactivity after postnatal reinfection with RSV due to aberrant cholinergic innervation of the respiratory tract and enhanced contractility of the airway smooth muscle. Furthermore, pups born to RSV-infected dams show selective impairment of innate anti-viral immunity, with virtual suppression of key Th1-type cytokines like IFN-? and IL-2. These changes persist after secondary reinfection and might provide a plausible explanation to the development of chronic airway dysfunction in children with history of severe RSV infections in infancy. Recently, data reported by us and by other investigators have increased significantly the translational potential of our preclinical studies, as there is growing evidence that RSV crosses the uterine-placental interface in humans and infects the fetal lungs by vertical transmission. This evidence challenges the paradigm that RSV infection is acquired only after birth and has shifted our attention to the prenatal effects of this virus, which may result in more severe and lasting consequences by interfering with lung development during a critical ?window of opportunity?.
The specific aims of the present proposal are organized around the evaluation of a central hypothesis articulated in the following components: 1. RSV infection vertically transmitted through the placenta from the infected mother to the fetus modifies expression and activity of key ion channels and receptors in the developing lungs, predisposing to postnatal airway hyperreactivity; 2. Unhealthy environmental conditions during pregnancy, such as unbalanced nutrition or exposure to particulate pollution, modulate vertical transmission of RSV to the fetus, and may amplify its long-term consequences in terms of airway hyperreactivity; and 3. In utero transmission of infective virus to the fetus occurs in humans, is associated with adverse perinatal respiratory outcomes, and might lead to persistent airway dysfunction and asthma in childhood.This research is likely to have a sustained and powerful impact because it will test the paradigm- shifting hypothesis that common respiratory viruses modulate lung development in humans and predispose to chronic respiratory pathology by infecting the fetus before birth. The proposed experiments are also designed to provide critical information concerning the influence of environmental factors on fetal lung development and the prenatal modulation of receptors essential to the control of airway function, and will correlate this information to the development of persistent airway hyperreactivity. This new information will contribute to a better understanding of the pathogenesis of highly prevalent diseases like bronchiolitis and asthma, and may lead to new and more precise preventative and therapeutic strategies, or to new indications for existing ones.
Until our 2013 paper proposing for the first time that the most common pediatric respiratory pathogen - respiratory syncytial virus (RSV) ? could spread from the mother airways to the fetal lungs via the placenta, it was universally accepted that fetal lungs were protected from maternal respiratory infections during gestation. In the previous funding cycle, we have shown proof of concept that this paradigm might be incorrect using animal models and cell cultures. A key innovation deriving from the present project will be the conclusive evidence that viruses like RSV, which usually causes only common colds in adult humans, can cross the human placenta, infect the human fetus during a highly vulnerable ?window of opportunity?, and modify the molecular structure of human lungs leading to persistent airway hyperreactivity. The new information deriving from this project will contribute to a better understanding of the pathogenesis and pathophysiology of highly prevalent diseases like infant bronchiolitis and childhood asthma, and may lead to new and more precise preventative and therapeutic strategies, or to new indications for existing ones.
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