ABSTRACT
Human African trypanosomiasis is a neglected disease caused by Trypanosoma brucei spp. A parasite cation pump (Ca(2+) ATPase; TBCA2) essential for survival and cation homeostasis was identified and characterized. It was hypothesized that targeting this pump using a Vibrio cholerae ghost (VCG)-based vaccine could protect against murine T. brucei infection. mRNA and protein expression of TBCA2 was differentially expressed in blood and insect stages of parasites and immunolocalized in the pericellular membrane and the flagellar pocket of bloodstream forms. Antigen-specific antibodies and Th1 cytokines, interleukin-2, interferon-gamma, and tumor necrosis factor-alpha were induced in rVCG-TBCA2-immunized mice and in vitro on antigen stimulation of splenic immune T cells, but the corresponding Th2-type response was unremarkable. Despite an increased median survival of 6 days in vaccinated mice, the mice were not protected against infection. Thus, immunization of mice produced robust parasite-specific antibodies but failed to protect mice against parasite challenge.
Subject(s)
Antigens, Protozoan/metabolism , Calcium-Transporting ATPases/metabolism , Trypanosoma brucei brucei/enzymology , Trypanosomiasis, African/immunology , Vibrio cholerae/genetics , Animals , Antibodies, Protozoan/blood , Antigens, Protozoan/immunology , Calcium-Transporting ATPases/immunology , Female , Gene Expression Regulation, Enzymologic , Mice , Mice, Inbred BALB C , Protozoan Vaccines/immunology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Vibrio cholerae/immunology , Vibrio cholerae/metabolismABSTRACT
Immunity to intracellular microbial pathogens, including Chlamydia species, is controlled primarily by cell-mediated effector mechanisms, yet, the absence of antibodies results in inefficient microbial clearance. We investigated the hypothesis that certain Fc receptor functions promote the rapid induction of elevated T helper type 1 (Th1) response, which effectively clears chlamydiae. FcR(-/-) mice exhibited a delayed and reduced frequency of Chlamydia-specific Th1 cells, compared to FcR(+/+) mice. In vitro, antichlamydial antibodies increased the rate of Th1 activation by FcR(+/+) but not FcR(-/-) antigen-presenting cells. FcR(-/-) dendritic cells and the T cell-associated IgG2A and IgA mediate enhanced Th1 activation by antibodies. Immunization with chlamydia-antibody complexes induced elevated and protective Th1 response. These results provide a mechanistic basis for requiring both T cell and humoral immune responses in protective immunity and vaccine evaluation. Findings offer a paradigm in host defense wherein different effector components function indirectly to maximize the principal effector mechanism.
Subject(s)
Chlamydia Infections/immunology , Receptors, Fc/immunology , Th1 Cells/immunology , Animals , Antibodies, Bacterial/immunology , Antigens, Bacterial/immunology , Chlamydia/immunology , Dendritic Cells/immunology , Female , Gene Deletion , Genitalia, Female/immunology , Genitalia, Female/microbiology , Lymphocyte Activation/immunology , Mice , Mice, Knockout , Mucous Membrane/immunology , Mucous Membrane/microbiology , Receptors, Fc/geneticsABSTRACT
An efficacious vaccine is needed to control the morbidity and burden of rising healthcare costs associated with genital Chlamydia trachomatis infection. Despite considerable efforts, the development of reliable chlamydial vaccines using conventional strategies has proven to be elusive. The 40kDa major outer membrane protein (MOMP) of C. trachomatis is so far the most promising candidate for a subunit vaccine. The lack of satisfactory protective immunity with MOMP-based vaccine regimens to date would suggest that either MOMP alone is inadequate as a vaccine candidate or better delivery systems are needed to optimize the effect of MOMP. Recombinant Vibrio cholerae ghosts (rVCG) are attractive for use as non-living vaccines because they possess strong adjuvant properties and are excellent vehicles for delivery of antigens of vaccine relevance to mucosal sites. The suitability of the ghost technology for designing an anti-chlamydial vaccine was evaluated by constructing a rVCG vector-based candidate vaccine expressing MOMP (rVCG-MOMP) and assessing vaccine efficacy in a murine model of C. trachomatis genital infection. Intramuscular delivery of the rVCG-MOMP vaccine induced elevated local genital mucosal as well as systemic Th1 responses. In addition, immune T cells from immunized mice could transfer partial protection against a C. trachomatis genital challenge to nai;ve mice. These results suggest that rVCG expressing chlamydial proteins may constitute a suitable subunit vaccine for inducing an efficient mucosal T cell response that protects against C. trachomatis infection. Altogether, the potency and relatively low production cost of rVCG offer a significant technical advantage as a chlamydial vaccine.
