The family Flaviviridae includes hemorrhagic fever viruses (e.g. dengue viruses, yellow fever virus) and encephalitis viruses (e.g. West Nile virus, Japanese encephalitis viruses). The long-term objective of this project is to determine the effect of flavivirus-specific CD4+ and CD8+ T cell responses induced by primary flavivirus infection on the immune response to subsequent infection with related flaviviruses.
In Specific Aim 1, we will characterize effector responses, TCR avidity and signaling to homologous and heterologous virus CD4+ and CD8+ T cell epitopes in primary flavivirus-immune individuals.
In Specific Aim 2, we will generate primary flavivirus CD4+ and CD8+ T cell responses to variant epitopes from flavivirus-naTve individuals and in human HLA transgenic mice. We will characterize cross-reactivity as in Aim 1 and will compare our findings in vitro to those generated in vivo.
In Specific Aim 3, we will determine the biologic relevance of our in vitro findings. We will define variant specific responses in humans with sequential flavivirus infections. Using human HLA transgenic mice, we will model primary and secondary responses using peptide immunization followed by subclinical West Nile virus infection. Lastly, in collaboration with Project 2, we will determine the effect of variant T cell stimulation of human T cells on primary human endothelial cells. These studies will help to elucidate mechanisms of cross-protection and may give insights into disease pathogenesis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of Massachusetts Medical School Worcester
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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
Yin, Liusong; Stern, Lawrence J (2014) Measurement of Peptide Binding to MHC Class II Molecules by Fluorescence Polarization. Curr Protoc Immunol 106:5.10.1-12
Townsley, Elizabeth; Woda, Marcia; Thomas, Stephen J et al. (2014) Distinct activation phenotype of a highly conserved novel HLA-B57-restricted epitope during dengue virus infection. Immunology 141:27-38

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