Giovanni Piedimonte, M.D.
Institute Chair, Children's Hospital and Pediatrics
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 444-2344
We have found evidence that RSV infection spreads transplacentally from the respiratory tract of the mother to the fetus.This evidence challenges the current paradigm that RSV infection is acquired only after birth and has shifted our attention to the prenatal and epigenetic effects of the virus, which may result in more severe and lasting consequences by interfering with critical developmental processes. The specific goals of our research are organized around the evaluation of a central hypothesis articulated in the following 3 components: 1. RSV infection is vertically transmitted through the placenta from the infected mother to the fetus during pregnancy, and viral genomic sequences persist post-natally in the offspring lungs; 2. Pre-natal exposure to the virus alters the expression of key neurotrophic factors and receptors in the developing respiratory tract, with long-term consequences in terms of airway inflammation and hyperreactivity; and 3. RSV infection modulates neurotrophic pathways epigenetically, with specific microRNAs (miRNAs) playing a central role that can be targeted pharmacologically. This project is likely to have a sustained and powerful impact because it will test the paradigm-shifting hypothesis that common respiratory viruses modulate lung development and predispose to chronic respiratory pathology by infecting the fetus before birth and by persisting in the lung tissues after birth. The proposed experiments are also designed to provide critical information concerning the pre-natal epigenetic modulation of neurotrophic factors essential to the development of airway innervation, and will correlate this information to the development of immune and inflammatory responses, as well as to chronic airway hyperreactivity.
In other words ...
The primary goal of our research is to define the interactions between genetic and environmental factors taking place during fetal life and/or during the very first days or weeks after birth - that determine the risk for a child to develop chronic lifelong diseases like asthma. In particular, we are interested in the role played by respiratory syncytial virus (RSV) - the most important respiratory virus in infancy and early childhood - because strong epidemiologic evidence links this infection with subsequent asthma. Recently, we found that RSV-induced disruption of certain molecules called neurotrophins during early development leads to short- and long-term changes in the distribution and reactivity of nerves across the respiratory tract, participating to the establishment of airway inflammation and hyperreactivity during and after the infection.
- Hu, C., K. Wedde-Beer, A. Auais, M. M. Rodriguez, and G. Piedimonte. 2002. Nerve growth factor and nerve growth factor receptors in respiratory syncytial virus-infected lungs, American Journal of Physiology 283: L494-L502.
- Tortorolo, L., A. Langer, G. Polidori, G. Vento, B. Stampachiacchere, L. Aloe, G. Piedimonte. 2005. Neurotrophins overexpression in lower airways of infants with respiratory syncytial virus infection, American Journal of Respiratory and Critical Care Medicine 172:233-237.
- Othumpangat, S., L. Gibson, L. Samsell, and G. Piedimonte. 2009. NGF is an essential survival factor for bronchial epithelial cells during respiratory syncytial virus infection, PLoS ONE 4:e6444.
- Rezaee, F., L. F. Gibson, D. Piktel, S. Othumpangat, and G. Piedimonte. 2011. Respiratory syncytial virus infection in human bone marrow stromal cells, American Journal of Respiratory Cell and Molecular Biology 45:277-286.
- Othumpangat, S., C. Walton, and G. Piedimonte. 2012. MicroRNA-221 modulates RSV replication in human bronchial epithelial cells by targeting NGF expression, PLoS ONE 7:e30030.