Abstract

Sexually transmitted diseases (STDs) pose one of the greatest threats to human lives worldwide, and yet there are no vaccines against STD agents. Currently, the process that leads to effective immune responses in the genital mucosa is poorly understood. Cytotoxic T lymphocyte (CTL) plays a pivotal role in defense against intracellular pathogens. The goal of the proposed study is to examine the anatomical, cellular and molecular mechanisms by which the antigen presenting dendritic cells (DCs) at the site of vaccination influence the establishment of effective CTL responses in the female genital mucosa. Toward this end, we propose to employ a mouse model of genital herpes in which the female mice are infected with herpes simplex virus (HSV) type 2 through its natural route of infection, the vaginal tract. In this proposal, we describe systematic approaches to examine how replication competent vs. defective attenuated HSV vaccines given via various immunization routes induce the mobilization of antigen-specific CD8+ T cells to the genital mucosa, and to analyze the importance of tissue DCs in conferring such capacities in CTLs. Further, the cellular requirement for the innate recognition of the viral vaccine vectors through Toll-like receptors will be examined.
The first aim will examine the expression of vaccine antigens and the role of DC subsets in CD8+ T cell priming following immunization through various routes of administration.
The second aim will examine how the DCs at the sites of immunization influences the distribution and function of memory CD8+ T cells in the vaginal mucosal tissues.
A final aim will determine the requirement for innate recognition of the vaccine vectors in establishing antiviral CTLs in the genital mucosa. Since productive establishment of CTL responses is important in defense against many intracellular STD agents, the knowledge gained from the proposed studies will provide critical basic and practical insights to a variety of STD vaccine approaches. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062428-04
Application #
7347009
Study Section
Special Emphasis Panel (ZRG1-VMD (01))
Program Officer
Ahlers, Jeffrey D
Project Start
2005-05-15
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$380,205
Indirect Cost

  Institution

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

  Publications

Khoury-Hanold, William; Yordy, Brian; Kong, Philip et al. (2016) Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality. Cell Host Microbe 19:788-99
Iijima, Norifumi; Iwasaki, Akiko (2016) Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Nature 533:552-6
Pillai, Padmini S; Molony, Ryan D; Martinod, Kimberly et al. (2016) Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science 352:463-6
Khoury-Hanold, William; Iwasaki, Akiko (2016) Autophagy Snuffs a Macrophage's Inner Fire. Cell Host Microbe 19:9-11
Kumamoto, Yosuke; Hirai, Toshiro; Wong, Patrick W et al. (2016) CD301b(+) dendritic cells suppress T follicular helper cells and antibody responses to protein antigens. Elife 5:
Gopinath, Smita; Kumamoto, Yosuke; Iwasaki, Akiko (2016) O-linked sugars sound the alarm. Nat Immunol 17:119-20
Shin, Haina; Kumamoto, Yosuke; Gopinath, Smita et al. (2016) CD301b+ dendritic cells stimulate tissue-resident memory CD8+ T cells to protect against genital HSV-2. Nat Commun 7:13346
Iijima, Norifumi; Iwasaki, Akiko (2015) Tissue instruction for migration and retention of TRM cells. Trends Immunol 36:556-64
Lipovsky, Alex; Zhang, Wei; Iwasaki, Akiko et al. (2015) Application of the proximity-dependent assay and fluorescence imaging approaches to study viral entry pathways. Methods Mol Biol 1270:437-51
Iwasaki, Akiko; Medzhitov, Ruslan (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-53

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