cell responses are elicited to some but not all possible targets of the immune response, and the rules that govern epitope selection are not completely clear. The main goals of this grant application are first to investigate epitope selection in the human T cell response to pathogens and second to investigate mechanisms of pathogens that affect epitope selection. Vaccinia virus and human herpesvirus 6 will be used as model pathogens. These are large-genome DMA viruses with many potential epitopes for which questions of epitope selection and immune hierarchy are particularly relevant. The proposal has three specific aims.
Aim 1 is to determine factors that control epitope selection of the human CD4+ T cell response by using vaccinia virus as a model. Several potential factors affecting epitope selection will be evaluated, including peptide-MHC dissociation kinetics, antigen expression level and location in the infected cell and/or viral particle, and whether the antigen is processed using conventional endosomal processing or autophagy pathways.
Aim 2 is to characterize the human CD4+ and CD8+ T cell response to HHV-6 virus. HHV-6 is a relatively recently discovered beta herpesvirus that establishes a long-lasting latent infection, and most people are carriers as a results of childhood exposure. Viral reactivation can occur under immunosuppressive conditions such a post-transplantation therapy or AIDS. Despite the central role of cellular immunity in controlling this virus, very little is known about the T cell response. In work directed at Aim 2, we will characterized the T cell response to HHV-6, study its specificity, and determine if factors important in epitope selection in vaccinia virus also apply to HHV-6. Many viruses have mechanisms to evade or modulate the immune response against them.
AIM 3 is to characterize modulation of antigen processing and presentation pathways in vaccinia-infected cells, and to determine whether HHV-6 also has mechanisms to alter antigen processing pathways in infected cells.
T cells are an important component of the protective immunity against many pathogens and characterization of the targets of the T cell response is central to the understanding of protective immune responses. Studies in this research grant will help to understand which parts of a virus are selected for targeting by T cells, We will characterize T cell responses to vaccinia virus, the virus used as a vaccine for smallpox, and responses to HHV-6 virus, a recently discovered virus associated with roseola and complications of transplant rejection.
|Canetta, Sarah E; Bao, Yuanyuan; Co, Mary Dawn T et al. (2014) Serological documentation of maternal influenza exposure and bipolar disorder in adult offspring. Am J Psychiatry 171:557-63|
|Thompson, Mikayla R; Sharma, Shruti; Atianand, Maninjay et al. (2014) Interferon ?-inducible protein (IFI) 16 transcriptionally regulates type i interferons and other interferon-stimulated genes and controls the interferon response to both DNA and RNA viruses. J Biol Chem 289:23568-81|
|Mathew, Anuja; Townsley, Elizabeth; Ennis, Francis A (2014) Elucidating the role of T cells in protection against and pathogenesis of dengue virus infections. Future Microbiol 9:411-25|
|Yin, Liusong; Trenh, Peter; Guce, Abigail et al. (2014) Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide. J Biol Chem 289:23449-64|
|Parra, Miguel; Herrera, Daniel; Calvo-Calle, J Mauricio et al. (2014) Circulating human rotavirus specific CD4 T cells identified with a class II tetramer express the intestinal homing receptors ?4?7 and CCR9. Virology 452-453:191-201|
|Yin, Liusong; Stern, Lawrence J (2014) A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC(50) determination. J Immunol Methods 406:21-33|
|Schmidt, Madelyn R; McGinnes-Cullen, Lori W; Kenward, Sarah A et al. (2014) Modification of the respiratory syncytial virus f protein in virus-like particles impacts generation of B cell memory. J Virol 88:10165-76|
|Terajima, Masanori; Co, Mary Dawn T; Ennis, Francis A (2014) Age and different influenza viruses. Lancet Infect Dis 14:101|
|Outinen, T K; Mäkelä, S; Huttunen, R et al. (2014) Urine soluble urokinase-type plasminogen activator receptor levels correlate with proteinuria in Puumala hantavirus infection. J Intern Med 276:387-95|
|Co, Mary Dawn T; Terajima, Masanori; Thomas, Stephen J et al. (2014) Relationship of preexisting influenza hemagglutination inhibition, complement-dependent lytic, and antibody-dependent cellular cytotoxicity antibodies to the development of clinical illness in a prospective study of A(H1N1)pdm09 Influenza in children. Viral Immunol 27:375-82|
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