Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection in infants and young children. In addition, RSV causes serious disease in elderly and immune compromised individuals. Immunization against RSV is associated with enhanced disease and pulmonary eosinophilia following natural infection that is thought to be caused by an exuberant memory CD4 Th2 response. As a consequence, there is currently no approved RSV vaccine and detailed studies directed towards prevention of vaccine-associated disease are a necessary first step in the development of a safe and effective vaccine. The BALB/c mouse model of RSV infection faithfully mimics the human respiratory disease including the development of extensive lung inflammation and injury, pulmonary eosinophilia, and enhanced disease in mice previously immunized with either formalin inactivated (FI)-RSV or a recombinant vaccinia virus (vv) that expresses the attachment (G) glycoprotein. Memory CD4 T cells secreting Th2 cytokines are necessary for this response because their depletion eliminates eosinophilia. Recent studies have demonstrated that RSV- specific CD8 T cells can inhibit Th2-mediated pulmonary eosinophilia in vvG-primed mice by as yet unknown mechanisms. By taking advantage of our ability to track RSV G-specific CD4 T cells, we will determine the mechanism of memory CD8 T cell inhibition of RSV G-induced pulmonary eosinophilia. Importantly, recent work has provided evidence that vvG and FI-RSV immunization may induce RSV vaccine-enhanced disease via unique mechanisms. Therefore, we will also ascertain if RSV-specific memory CD8 T cells can prevent FI-RSV vaccine-enhanced disease. The overall goal of this proposal is to define the mechanism(s) of how RSV-specific memory CD8 T cells inhibit CD4 T cell-mediated RSV vaccine-enhanced disease and immunopathology. We propose the following Specific Aims: 1) To determine the how memory CD8 T cells inhibit RSV-specific memory Th2 cells and RSV vaccine-enhanced pulmonary eosinophilia and, 2) To determine if memory CD8 T cells can prevent FI-RSV vaccine-enhanced disease and pulmonary injury. The underlying mechanisms of RSV vaccine-enhanced disease remain unclear. The studies in this proposal are designed to determine the role of RSV-specific memory CD8 T cells in decreasing the severity of CD4 T cell-mediated immunopathology in a model system with direct relevance to human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063520-05
Application #
8013503
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Kim, Sonnie
Project Start
2007-02-15
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$349,408
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Knudson, Cory J; Hartwig, Stacey M; Meyerholz, David K et al. (2015) RSV vaccine-enhanced disease is orchestrated by the combined actions of distinct CD4 T cell subsets. PLoS Pathog 11:e1004757
McDermott, Daniel S; Knudson, Cory J; Varga, Steven M (2014) Determining the breadth of the respiratory syncytial virus-specific T cell response. J Virol 88:3135-43
Yang, Kejian; Varga, Steven M (2014) Mucosal vaccines against respiratory syncytial virus. Curr Opin Virol 6:78-84
Fulton, Ross B; Weiss, Kayla A; Pewe, Lecia L et al. (2013) Aged mice exhibit a severely diminished CD8 T cell response following respiratory syncytial virus infection. J Virol 87:12694-700
Olson, Matthew R; McDermott, Daniel S; Varga, Steven M (2012) The initial draining lymph node primes the bulk of the CD8 T cell response and influences memory T cell trafficking after a systemic viral infection. PLoS Pathog 8:e1003054
McDermott, Daniel S; Weiss, Kayla A; Knudson, Cory J et al. (2011) Central role of dendritic cells in shaping the adaptive immune response during respiratory syncytial virus infection. Future Virol 6:963-973
McDermott, Daniel S; Varga, Steven M (2011) Quantifying antigen-specific CD4 T cells during a viral infection: CD4 T cell responses are larger than we think. J Immunol 187:5568-76
Weiss, Kayla A; Christiaansen, Allison F; Fulton, Ross B et al. (2011) Multiple CD4+ T cell subsets produce immunomodulatory IL-10 during respiratory syncytial virus infection. J Immunol 187:3145-54
Fulton, Ross B; Varga, Steven M (2010) Editorial: CD8 T cells cut back on calcium intake in the lungs. J Leukoc Biol 87:961-4
Fulton, Ross B; Meyerholz, David K; Varga, Steven M (2010) Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J Immunol 185:2382-92

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