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-3 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-3 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-3 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-3 producing CPAF specific CD4+ T cells enhance bacterial clearance and prevent the development of urogenital pathology associated with chlamydial infection.
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-3 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.
|Wali, Shradha; Gupta, Rishein; Yu, Jieh-Juen et al. (2016) Guinea pig genital tract lipidome reveals in vivo and in vitro regulation of phosphatidylcholine 16:0/18:1 and contribution to Chlamydia trachomatis serovar D infectivity. Metabolomics 12:|
|Gupta, Rishein; Arkatkar, Tanvi; Keck, Jonathon et al. (2016) Antigen specific immune response in Chlamydia muridarum genital infection is dependent on murine microRNAs-155 and -182. Oncotarget 7:64726-64742|
|Lanka, Gopala Krishna Koundinya; Yu, Jieh-Juen; Gong, Siqi et al. (2016) IgA modulates respiratory dysfunction as a sequela to pulmonary chlamydial infection as neonates. Pathog Dis 74:|
|Arkatkar, Tanvi; Gupta, Rishein; Li, Weidang et al. (2015) Murine MicroRNA-214 regulates intracellular adhesion molecule (ICAM1) gene expression in genital Chlamydia muridarum infection. Immunology 145:534-42|
|Gupta, Rishein; Arkatkar, Tanvi; Yu, Jieh-Juen et al. (2015) Chlamydia muridarum infection associated host MicroRNAs in the murine genital tract and contribution to generation of host immune response. Am J Reprod Immunol 73:126-40|
|Wali, Shradha; Gupta, Rishein; Veselenak, Ronald L et al. (2014) Use of a Guinea pig-specific transcriptome array for evaluation of protective immunity against genital chlamydial infection following intranasal vaccination in Guinea pigs. PLoS One 9:e114261|
|Gupta, Rishein; Wali, Shradha; Yu, Jieh-Juen et al. (2014) In vivo whole animal body imaging reveals colonization of Chlamydia muridarum to the lower genital tract at early stages of infection. Mol Imaging Biol 16:635-41|
|Manam, Srikanth; Chaganty, Bharat K R; Evani, Shankar Jaikishan et al. (2013) Intranasal vaccination with Chlamydia pneumoniae induces cross-species immunity against genital Chlamydia muridarum challenge in mice. PLoS One 8:e64917|
|Kamalakaran, Sangamithra; Chaganty, Bharat K R; Gupta, Rishein et al. (2013) Vaginal chlamydial clearance following primary or secondary infection in mice occurs independently of TNF-?. Front Cell Infect Microbiol 3:11|
|Li, Weidang; Murthy, Ashlesh K; Lanka, Gopala Krishna et al. (2013) A T cell epitope-based vaccine protects against chlamydial infection in HLA-DR4 transgenic mice. Vaccine 31:5722-8|
Showing the most recent 10 out of 19 publications