There currently is no licensed vaccine against Chlamydia trachomatis, the leading cause of bacterial sexually transmitted disease worldwide. Untreated genital chlamydial infection cause serious sequelae such as pelvic inflammatory disease, ectopic pregnancy, and infertility. A Chlamydia-secreted protein, designated as CPAF (chlamydial protease/proteasome-like activity factor), is responsible for degradation of the host MHC transcription factors RFX5 and USF1. Inhibiting CPAF activity will therefore be a feasible vaccination strategy for blocking chlamydial evasion of immune recognition. We have now provided direct evidence to demonstrate the effectiveness of such an approach using recombinant (r)CPAF and IL-12 in an intranasal (i.n.) delivery system. Intranasal vaccination with rCPAF and IL-12 induced robust antigen-specific IFN-? production, significantly reduced bacterial shedding upon intravaginal (i.vag.) chlamydial challenge and significantly accelerated the resolution of infection compared to mock-immunized (PBS) mice. Importantly, rCPAF+IL-12 vaccinated mice exhibited protection against pathological consequences of chlamydial infection, including mesosalpingeal inflammation and development of hydrosalpinx and oviduct dilation. The rCPAF+IL-12-mediated resolution of chlamydial infection and protection against inflammatory pathology was highly dependent on endogenous IFN-? production and the action of antigen-specific CD4+ T cells. Based on our notable body of evidence, we hypothesize that "CPAF vaccination promotes preservation of fertility and reduces inflammatory pathology after genital Chlamydia infection by enhancing bacterial clearance within the upper genital tract via antigen-specific IFN-? secreting CD4+ T-cells with the participation of local phagocytic cells". We will test this hypothesis by;(1) Examining the direct effect of i.n. CPAF vaccination on the preservation of fertility after genital chlamydial challenge;(2) Determine the relationship between the reduction in chlamydial organisms and the infiltration of antigen-specific CD4+ T cells within the upper genital tract induced by CPAF vaccination;(3) Investigating the mechanism(s) by which IFN-? producing CPAF specific CD4+ T cells enhance bacterial clearance and prevent the development of urogenital pathology associated with chlamydial infection.

Public Health Relevance

There currently is no licensed vaccine against Chlamydia trachomatis, the leading cause of bacterial sexually transmitted disease worldwide. Using a murine model of genital chlamydial infection, intranasal vaccination with (recombinant chlamydial protease/proteasome-like activity factor) CPAF and IL-12 induced robust antigen-specific IFN-? production, significantly reduced bacterial shedding and induced protection against pathological consequences of chlamydial infection, including mesosalpingeal inflammation and development of hydrosalpinx and oviduct dilation. This proposal will further examine the efficacy of CPAF vaccination against the prevention of infertility and provide mechanistic insight into the nature of this protective immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074860-04
Application #
8197433
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Hiltke, Thomas J
Project Start
2008-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$354,061
Indirect Cost
$109,036
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
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Li, Weidang; Murthy, Ashlesh K; Guentzel, M Neal et al. (2010) Immunization with a combination of integral chlamydial antigens and a defined secreted protein induces robust immunity against genital chlamydial challenge. Infect Immun 78:3942-9
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