Natural Killer (NK) cells are primary effector cells of the innate immune response and play a critical role in the control of viral replication in several disease models. Depletions or deficiencies of NK cells lead to significantly more severe viral disease and death in both mice and humans. Killer immunoglobulin-like receptors (KIRs) interact with HLA class I ligands and play a central role in the regulation and activation of naturl killer (NK) cells. The interaction between KIRs and their HLA class I ligands can thus have a profound impact on the efficacy of NK cell-mediated control of viral pathogenesis and has been demonstrated for a number of chronic viral infections. Very little is known about the involvement of NK cells in regulating dengue virus infections. We have found that a CD8 T cell epitope on the non-structural protein 1 (NS1) of dengue interacts with a well characterized inhibitory receptor KIR3DL1 on NK cells. In this application, we will use the antigen-specific tetramers and peptides to dissect the interaction with KIR3DL1 and determine how dengue virus modulates the function of this important subset of NK cells. The studies outlined in this application will provide a better understanding of the importance of KIR-MHC class I interactions on NK cells and provide the rationale to target this innate arm of the immune response to control dengue virus replication.

Public Health Relevance

We will evaluate interactions between a well characterized inhibitory receptor KIR3DL1 on NK cells and a dengue virus peptide presented on HLA B57 and determine whether the NS1 peptide can modulate NK cell function. Our studies will provide a better understanding of the importance of KIR-MHC class I interactions in dengue virus pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AI113479-02
Application #
9151059
Study Section
Virology - B Study Section (VIRB)
Program Officer
Cassetti, Cristina
Project Start
2015-06-16
Project End
2017-05-31
Budget Start
2015-09-01
Budget End
2016-05-31
Support Year
2
Fiscal Year
2015
Total Cost
$194,990
Indirect Cost
$67,961
Name
University of Rhode Island
Department
Type
Other Domestic Higher Education
DUNS #
144017188
City
Kingston
State
RI
Country
United States
Zip Code
02881
Mathew, Anuja (2018) Regulation and Function of NK and T Cells During Dengue Virus Infection and Vaccination. Adv Exp Med Biol 1062:251-264
Drews, Elena; Adam, Awadalkareem; Htoo, Phone et al. (2018) Upregulation of HLA-E by dengue and not Zika viruses. Clin Transl Immunology 7:e1039
Mathew, Anuja (2018) Defining the role of NK cells during dengue virus infection. Immunology :
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