This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We hypothesize that the pathogenicity of RSV and hMPV LRI is enhanced by virus replication in activated immune and epithelial cells that coupled with an exuberant inflammatory response result in the severe disease seen. This response results in airway changes in the developing lung, and a combination of airway inflammation and remodeling leads to subsequent reactive airway disease. We will test this hypothesis by measuring the effects of tobacco smoke exposure, epidemiologic risk factors, viral replication and inflammatory responses (using differential gene analysis) on the development of severe RSV/hMPV LRI. Samples will be collected from children in each of 4 different groups: 1) nasal wash samples from 30 outptatient children with upper respiratory tract infections (URI) and/or mild lower respiratory tract infections (LRI), 2) nasal wash samples from 30 inpatient children with LRI, 3) nasal wash and tracheal aspirated from 30 intubated children with severe LRI, and 4) nasal wash and tracheal aspriates from 35 health infants (without respiratory symptoms) undergoing day surgery (these will serve as the negative control). Each group, aside from the health control group, will be comprised of 10 each with with RSV, hMPV or RSV and hMPV. Cytokine assessments in aspirates will be done to correlate the microarray analysis with protein production. We will follow subjects (except for control subjests) monthly over 1-1.5 years. We will perform infant pulmonary function tests (PFT's), at 1- 1.5 years. These in vivo and in vitro studies will define and characterize environmental, host, and viral factors involved in severe LRI and its progression to later reactive airways disease.
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