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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI057319-10
Application #
8452142
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$415,395
Indirect Cost
$155,700
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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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