Herpes simplex virus (HSV) type 2 is a common sexually transmitted viral agent which is the leading cause of genital ulcers. In the United States, the prevalence of this disease exceeds 45 million, affecting more women than men. Genital HSV-2 infection often results in the establishment of latency in the sacral root ganglia, with frequent reactivation and productive infection in the mucosal epithelium. Although HSV-2 is treated symptomatically with anti-viral agents such as acyclovir, currently no cure exists for this debilitating disease. The goal of the studies proposed is to define and understand the cellular and molecular mechanism of how protective immunity is generated to HSV-2 infection at the genital mucosal surfaces. Prior studies demonstrated that protective immunity is mediated by CD4+ T lymphocytes secreting IFNg. Data from our own studies revealed the critical importance of dendritic cells in generating Th1 responses following intravaginal HSV-2 infection. Further, we demonstrate that the activation of dendritic cells (DCs) and induction of Th1 responses during HSV-2 infection require toll-like receptor (TLR) signaling. With the use of a mouse model for genital herpes infection, this proposal will systematically define the intercellular and intracellular signals that govern the recruitment and activation of dendritic cells leading to priming of CD4+ T lymphocytes to secrete IFNg.
The first aim will assess the mechanism by which the dendritic cells are recruited to the sites of primary infection, and to evaluate the functional roles of distinct subsets of DCs in the generation of anti-HSV-2 immunity.
The second aim will systematically identify the TLRs that recognize HSV-2 and to determine the viral ligands that bind to the respective TLRs.
A final aim will examine the in vivo role of TLR-mediated recognition of HSV-2 by different host cell types. The proposed experiments will provide novel and critical information on the mechanism of generation of protective immunity within the female genital tract to HSV-2. Since productive Th1-based immunity is important in defense to most intracellular pathogens, the insights provided by the proposed studies should eventually aid in the designing of rational approaches to prevention of the spread of HSV-2 and other sexually transmitted diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054359-05
Application #
7316090
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Hiltke, Thomas J
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
5
Fiscal Year
2008
Total Cost
$266,144
Indirect Cost
Name
Yale University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yockey, Laura J; Iwasaki, Akiko (2018) Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development. Immunity 49:397-412
Gopinath, Smita; Kim, Myoungjoo V; Rakib, Tasfia et al. (2018) Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner. Nat Microbiol 3:611-621
Mihaylova, Valia T; Kong, Yong; Fedorova, Olga et al. (2018) Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus. Cell Rep 24:3000-3007.e3
Yockey, Laura J; Jurado, Kellie A; Arora, Nitin et al. (2018) Type I interferons instigate fetal demise after Zika virus infection. Sci Immunol 3:
Mohideen, Muneeb; Quijano, Elias; Song, Eric et al. (2017) Degradable bioadhesive nanoparticles for prolonged intravaginal delivery and retention of elvitegravir. Biomaterials 144:144-154
Lipovsky, Alex; Erden, Asu; Kanaya, Eriko et al. (2017) The cellular endosomal protein stannin inhibits intracellular trafficking of human papillomavirus during virus entry. J Gen Virol 98:2821-2836
Iwasaki, Akiko; Foxman, Ellen F; Molony, Ryan D (2017) Early local immune defences in the respiratory tract. Nat Rev Immunol 17:7-20
Iwasaki, Akiko (2017) Immune Regulation of Antibody Access to Neuronal Tissues. Trends Mol Med 23:227-245
Hastings, Andrew K; Yockey, Laura J; Jagger, Brett W et al. (2017) TAM Receptors Are Not Required for Zika Virus Infection in Mice. Cell Rep 19:558-568
Fink, Susan L; Jayewickreme, Teshika R; Molony, Ryan D et al. (2017) IRE1? promotes viral infection by conferring resistance to apoptosis. Sci Signal 10:

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