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.
|Mathew, Anuja (2017) Humanized mouse models to study human cell-mediated and humoral responses to dengue virus. Curr Opin Virol 25:76-80|
|Ramirez, Alejandro; Co, Mary; Mathew, Anuja (2016) CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice. PLoS One 11:e0150425|
|Townsley, E; O'Connor, G; Cosgrove, C et al. (2016) Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells. Clin Exp Immunol 183:419-30|
|Woda, Marcia; Friberg, Heather; Currier, Jeffrey R et al. (2016) Dynamics of Dengue Virus (DENV)-Specific B Cells in the Response to DENV Serotype 1 Infections, Using Flow Cytometry With Labeled Virions. J Infect Dis 214:1001-9|
|Tervo, Laura; Mäkelä, Satu; Syrjänen, Jaana et al. (2015) Smoking is associated with aggravated kidney injury in Puumala hantavirus-induced haemorrhagic fever with renal syndrome. Nephrol Dial Transplant 30:1693-8|
|Woda, Marcia; Mathew, Anuja (2015) Fluorescently labeled dengue viruses as probes to identify antigen-specific memory B cells by multiparametric flow cytometry. J Immunol Methods 416:167-77|
|Becerra-Artiles, Aniuska; Dominguez-Amorocho, Omar; Stern, Lawrence J et al. (2015) A Simple Proteomics-Based Approach to Identification of Immunodominant Antigens from a Complex Pathogen: Application to the CD4 T Cell Response against Human Herpesvirus 6B. PLoS One 10:e0142871|
|Jaiswal, Smita; Smith, Kenneth; Ramirez, Alejandro et al. (2015) Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice. Exp Biol Med (Maywood) 240:67-78|
|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|
|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|
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