My career goals are focused upon a disease, Respiratory Syncytial Virus (RSV) infection, the most important respiratory pathogen of early childhood. Deepening our understanding of this disease and developing treatmen and control strategies are my long term goals. With this focus, I am committed to translational clinical research but need to acquire specific skills that will allow me to be most effective in this area. This award will allow me to accomplish this in the following ways. First, I will increase my knowledge of immunology through course work, seminars and workshops. Second, I will develop the skills necessary to conduct clinical research by taking specific didactic courses including clinical trial design, data management and statistical analysis. Third, my research project will serve both to solidify knowledge gained in the classroom and to develop essential laboratory techniques. Furthermore it will do this while simultaneously advancing the understanding of RSV pathogenesis. Due in part to the lack of a parallel animal model, my research project focuses on the pathogenesis of RSV directly in infected infants. The severity of disease caused by acute RSV infection varies widely, yet the factors influencing which previously healthy children develop severe disease are not well understood. Like an increasing number of infectious diseases, RSV disease severity is likely to be influenced by genetic differences controllin the immune response. To answer the mechanistic question of whether RSV disease severity is controlled by preexisting immunogenetic mechanisms and whether these mechanisms act through allowing increased viral replication, I will study the relationships between immunogenetics, the kinetics of viral replication and disease severity in infants with RSV infection of varying seventy. An effective immune response to viral infection involves secretion of the Th1 cytokines Tumor Necrosis Factor alpha (TNFalpha) and Interferon Gamma (IFNgamma). will assess polymorphisms associated with these cytokine genes in the expectation that infants who are Th1 channeled, having TNFalpha and or IFNgamma high secretor polymorphisms, will be able to more readily control early viral replication, will have lower RSV loads and will have lower disease severity. During the 5 year research plan, I also propose to study early RSV disease and to define a population which has viral load, genetic and othe markers predictive of responding to RSV therapies. In short, I have designed and structured all aspects of this proposal to advance my career goal: deepening our understanding of RSV disease and the means to control it. With the help of this award, this goal can be achieved.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Center for Research Resources Initial Review Group (RIRG)
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Wilde, David B
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University of Tennessee Health Science Center
Schools of Medicine
United States
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Thompson, Tonya M; Roddam, Philippa L; Harrison, Lisa M et al. (2015) Viral Specific Factors Contribute to Clinical Respiratory Syncytial Virus Disease Severity Differences in Infants. Clin Microbiol 4:
Kim, Young-In; Murphy, Ryan; Majumdar, Sirshendu et al. (2015) Relating plaque morphology to respiratory syncytial virus subgroup, viral load, and disease severity in children. Pediatr Res 78:380-8
Kim, Young-In; DeVincenzo, John P; Jones, Bart G et al. (2014) Respiratory syncytial virus human experimental infection model: provenance, production, and sequence of low-passaged memphis-37 challenge virus. PLoS One 9:e113100
El Saleeby, Chadi M; Bush, Andy J; Harrison, Lisa M et al. (2011) Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children. J Infect Dis 204:996-1002
DeVincenzo, John P; Wilkinson, Tom; Vaishnaw, Akshay et al. (2010) Viral load drives disease in humans experimentally infected with respiratory syncytial virus. Am J Respir Crit Care Med 182:1305-14
El Saleeby, Chadi M; Li, Rongling; Somes, Grant W et al. (2010) Surfactant protein A2 polymorphisms and disease severity in a respiratory syncytial virus-infected population. J Pediatr 156:409-14
Miyairi, Isao; DeVincenzo, John P (2008) Human genetic factors and respiratory syncytial virus disease severity. Clin Microbiol Rev 21:686-703
DeVincenzo, John P (2005) Factors predicting childhood respiratory syncytial virus severity: what they indicate about pathogenesis. Pediatr Infect Dis J 24:S177-83, discussion S182
Perkins, Stephanie M; Webb, David L; Torrance, Shauna A et al. (2005) Comparison of a real-time reverse transcriptase PCR assay and a culture technique for quantitative assessment of viral load in children naturally infected with respiratory syncytial virus. J Clin Microbiol 43:2356-62
Devincenzo, John P (2004) Natural infection of infants with respiratory syncytial virus subgroups A and B: a study of frequency, disease severity, and viral load. Pediatr Res 56:914-7

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