Respiratory syncytial virus (RSV) is a major pathogen leading to morbidity and mortality among infants, substantial children and adults. The pathogenesis of human RSV infection is incompletely understood. RSV is also a problematic nosocomial pathogen. The past study of the epidemiology of nosocomial RSV infections has been limited by difficulty in accurately identifying specific viral strains. The identification of specific genetic markers associated with RSV virulence will provide greater understanding of RSV pathogenesis and epidemiology. The goals of the project's research components are: (i) determine the association between RSV genotype and host severity of illness, (ii) determine if RSV quasispecies are present during human infection and if they impact clinical outcomes, (iii) identify and characterize RSV strains resistant to palivizumab neutralization and (iv) apply the technical capability of genotyping RSV strains to study the epidemiology of nosocomial RSV and determine whether the routine practice of cohorting hospitalized RSV patients places them at risk for the acquisition of nosocomial RSV due to discordant strains. Phylogenetic analysis of the RSV G gene nucleotide sequence will be used to derive genotype assignments. The severity of illness will be quantified using a composite severity score. The presence of quasispecies will be identified using heteroduplex mobility assays. Quasispecies will be characterized by the sequencing of RSV genes subcloned onto plasmids. Microneutralization assays will be performed to screen RSV isolates from patients receiving palivizumab for resistance to palivizumab neutralization. The mutation(s) encoding palivizumab resistance will be characterized by sequence analysis. A structured research training program is planned to permit growth into an independent investigator performing patient-oriented, interdisciplinary research in healthcare epidemiology using the analytical and laboratory tools of genetics and molecular evolution. Training will include graduate level courses through the Departments of Genetics, Ecology and Evolutionary Biology and the School of Medicine at Yale University. There will be participation in clinical and research seminars in addition to formal presentations of ongoing research both at Yale University and national meetings. A committee consisting of established basic scientists, clinical researchers and hospital epidemiology mentors has been established to provide scientific guidance and training oversight.
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