Mechanisms that link innate and adaptive immunity play a central role in immune responsiveness and are a promising area of investigation for the discovery of novel immune adjuvants. In the oral cavity, human beta defensins that are produced by epithelial cells may mediate crosstalk between innate and adaptive defenses. These molecules have anti-microbial properties but also mediate chemotaxis of antigen-presenting cells. Our work has characterized for the first time, the ability of human beta defensin-3 to activate antigenpresenting cells in a toll-like receptor-dependent manner. The proposed studies will explore the effects of this interaction in the maturation of human antigen-presenting cells and in the development of T cell immunity. Cell signaling assays and proteomics analyses will be utilized to ascertain the effects of beta defensin-3 in human antigen-presenting cells and to compare these responses with those induced by other toll-like receptor agonists. The function and phenotype of naTve T cells will also be assessed after activation of these cells with beta defensin-primed antigen-presenting cells. The proposed studies include a determination of the structural properties of human beta defensin-3 that account for its toll-like receptor agonist activity. These studies involve utilization of chimeric and mutated defensin molecules to examine their toll-like receptor agonist activity. Finally, the proposed studies examine the responsiveness of antigenpresenting cells from HIV-infected persons to the activating signals provided by beta defensin-3 and other toll-like receptor agonists to explore the hypothesis that reduced responsiveness to beta defensins in HIV disease may predispose these persons to oral complications. These studies have important implications for developing defensin molecules as oral vaccine adjuvants and for understanding defensin biology in the context of chronic HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Program Projects (P01)
Project #
5P01DE019759-05
Application #
8462467
Study Section
Special Emphasis Panel (ZDE1-JH)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$287,476
Indirect Cost
$104,391
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
DasGupta, Twishasri; Nweze, Emeka I; Yue, Hong et al. (2016) Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53. Oncotarget 7:27430-44
Zapata, Wildeman; Aguilar-Jiménez, Wbeimar; Feng, Zhimin et al. (2016) Identification of innate immune antiretroviral factors during in vivo and in vitro exposure to HIV-1. Microbes Infect 18:211-9
Judge, Chelsey J; Reyes-Aviles, Elane; Conry, Sara J et al. (2015) HBD-3 induces NK cell activation, IFN-γ secretion and mDC dependent cytolytic function. Cell Immunol 297:61-8
Feng, Zhimin; Jia, Xun; Adams, Mark D et al. (2014) Epithelial innate immune response to Acinetobacter baumannii challenge. Infect Immun 82:4458-65
Chung, Charlotte Y; Alden, Stephanie L; Funderburg, Nicholas T et al. (2014) Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog 10:e1004198
Willie, B; Hall, N B; Stein, C M et al. (2014) Association of Toll-like receptor polymorphisms with HIV status in North Americans. Genes Immun 15:569-77
Cheruvu, Vinay K; Igo Jr, Robert P; Jurevic, Richard J et al. (2014) African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 66:102-7
Mehlotra, R K; Zimmerman, P A; Weinberg, A et al. (2013) Variation in human β-defensin genes: new insights from a multi-population study. Int J Immunogenet 40:261-9
Golden, Jackelyn B; McCormick, Thomas S; Ward, Nicole L (2013) IL-17 in psoriasis: implications for therapy and cardiovascular co-morbidities. Cytokine 62:195-201
Ghosh, Santosh K; McCormick, Thomas S; Eapen, Betty L et al. (2013) Comparison of epigenetic profiles of human oral epithelial cells from HIV-positive (on HAART) and HIV-negative subjects. Epigenetics 8:703-9

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