This exploratory R21 application will investigate the significance of the newly described """"""""Th17 axis of immunity"""""""" in a mouse model of vaginal gonococcal infection. The objectives are to determine whether Neisseria gonorrhoeae can induce the development of Th17 cells and to test the hypothesis that signaling through the interleukin (IL)-17 receptor is important in the elicitation of the innate immune response. Th17 cells, which produce IL-17, have been shown to play a major role in innate immune/inflammatory responses and in the elicitation of the neutrophil influx in response to mucosal infections. N. gonorrhoeae, the agent of gonorrhea, typically induces a neutrophil influx into the site of infection and the presence in genital secretions of gonococci associated with neutrophils is a classic diagnostic criterion. Like other pathogens, N. gonorrhoeae interacts with host tissues to elicit responses that favor its survival, and the natural infection does not induce protective immunity against repeated infection. It has therefore been suggested that N. gonorrhoeae actively interferes with the development of adaptive immune responses, and it is hypothesized that the elicitation of Th17 cells contributes to this.
The Specific Aims are: (1) To evaluate the ability of N. gonorrhoeae to induce the development of Th17 cells and the production of key cytokines in mouse cells in vitro and in vivo, and in human blood mononuclear cells in vitro;(2) To compare the responses of normal wild- type and IL-17 receptor-deficient mice to vaginal challenge with N. gonorrhoeae in order to determine whether signalling through this receptor is critical in the recruitment of neutrophils and in deflecting adaptive immune responses. Elucidation of this novel pathway of the host response to N. gonorrhoeae will greatly improve comprehension of the immuno-pathogenic mechanisms of gonococcal infection and facilitate the development of new interventions against gonorrhea, for which there is a demonstrable need.

Public Health Relevance

Gonorrhea is the second-most-frequent, notifiable infectious disease in the United States and the CDC reports over 300,000 cases in recent years [59], although the true incidence is believed to be double that figure;world- wide incidence is estimated to be over 60 million new infections per year [60]. Women bear the brunt of the infection which can lead to serious reproductive health problems including pelvic inflammatory disease, infertility, and risk for ectopic pregnancy, and while it is well known that gonorrhea does not generate immunity to repeated infection, no vaccines exist to control it and antibiotic resistance is spreading. This proposal will apply important new findings from the field of immunology to determine the way in which the immune system interacts with the gonococcus bacterium, an area that is poorly understood at present.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI074791-02
Application #
7760941
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Hiltke, Thomas J
Project Start
2009-02-01
Project End
2013-01-31
Budget Start
2010-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2010
Total Cost
$196,144
Indirect Cost
Name
State University of New York at Buffalo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Jerse, Ann E; Bash, Margaret C; Russell, Michael W (2014) Vaccines against gonorrhea: current status and future challenges. Vaccine 32:1579-87
Liu, Y; Liu, W; Russell, M W (2014) Suppression of host adaptive immune responses by Neisseria gonorrhoeae: role of interleukin 10 and type 1 regulatory T cells. Mucosal Immunol 7:165-76
Liu, Yingru; Egilmez, Nejat K; Russell, Michael W (2013) Enhancement of adaptive immunity to Neisseria gonorrhoeae by local intravaginal administration of microencapsulated interleukin 12. J Infect Dis 208:1821-9
Liu, Y; Islam, E A; Jarvis, G A et al. (2012) Neisseria gonorrhoeae selectively suppresses the development of Th1 and Th2 cells, and enhances Th17 cell responses, through TGF-?-dependent mechanisms. Mucosal Immunol 5:320-31
Woof, J M; Russell, M W (2011) Structure and function relationships in IgA. Mucosal Immunol 4:590-7
Liu, Yingru; Russell, Michael W (2011) Diversion of the immune response to Neisseria gonorrhoeae from Th17 to Th1/Th2 by treatment with anti-transforming growth factor ? antibody generates immunological memory and protective immunity. MBio 2:e00095-11
Feinen, B; Jerse, A E; Gaffen, S L et al. (2010) Critical role of Th17 responses in a murine model of Neisseria gonorrhoeae genital infection. Mucosal Immunol 3:312-21
Russell, Michael W; Mestecky, Jiri (2010) Tolerance and protection against infection in the genital tract. Immunol Invest 39:500-25
Mestecky, Jiri; Russell, Michael W (2009) Specific antibody activity, glycan heterogeneity and polyreactivity contribute to the protective activity of S-IgA at mucosal surfaces. Immunol Lett 124:57-62