Abstract
Recently, we reported that our PPM chlamydial nanovaccine [a biodegradable co-polymeric PLA-PEG (poly(lactic acid)-poly(ethylene glycol))-encapsulated M278 peptide (derived from the major outer membrane protein (MOMP) of Chlamydia)] exploits the caveolin-mediated endocytosis pathway for endosomal processing and MHC class II presentation to immune-potentiate Chlamydia-specific CD4+ T-cell immune effector responses. In the present study, we employed the Chlamydia muridarum mouse infection model to evaluate the protective efficacy of PPM against a genital tract challenge. Our results show that mice immunized with PPM were significantly protected against a homologous genital tract challenge evidently by reduced vaginal bacterial loads. Protection of mice correlated with enhanced Chlamydia-specific adaptive immune responses predominated by IFN-γ along with CD4+ T-cells proliferation and their differentiation to CD4+ memory (CD44high CD62Lhigh) and effector (CD44high CD62Llow) T-cell phenotypes. We observed the elevation of M278- and MOMP-specific serum antibodies with high avidity in the ascending order IgG1 > IgG2b > IgG2a. A key finding was the elevated mucosal IgG1 and IgA antibody titers followed by an increase in MOMP-specific IgA after the challenge. The Th1/Th2 antibody titer ratios (IgG2a/IgG1 and IgG2b/IgG1) revealed that PPM evoked a Th2-directed response, which skewed to a Th1-dominated antibody response after the bacterial challenge of mice. In addition, PPM immune sera neutralized the infectivity of C. muridarum in McCoy cells, suggesting the triggering of functional neutralizing antibodies. Herein, we reveal for the first time that subcutaneous immunization with the self-adjuvanting biodegradable co-polymeric PPM nanovaccine immune-potentiated robust CD4+ T cell-mediated immune effector responses; a mixed Th1 and Th2 antibody response and local mucosal IgA to protect mice against a chlamydial genital tract challenge.
Highlights
Chlamydia trachomatis is an obligate, Gram-negative bacterium residing in the human genital tract and the leading bacterial sexually-transmitted infections worldwide [1]
We recently reported that the PPM nanovaccine immunepotentiates innate and adaptive immune responses in immunized mice [36, 40]
Given that PPM triggered adaptive cellular and humoral immune response correlates of Chlamydia protective immunity in mice, we hypothesized that PPM would be efficacious in providing protection against a chlamydial genital challenge infection
Summary
Chlamydia trachomatis is an obligate, Gram-negative bacterium residing in the human genital tract and the leading bacterial sexually-transmitted infections worldwide [1]. Unsuccessful strategies of live, inactivated, or attenuated bacteria [9,10,11] as vaccine targets have prompted a switch toward subunit-based vaccine candidates [4, 6, 7, 12,13,14,15,16,17,18,19,20] Prominent amongst these is the major outer membrane protein (MOMP) of Chlamydia that is highly enriched with multiple T- and B-cell epitopes, expressed throughout the bacterium developmental cycle [6, 21]. Reports have shown that MOMP triggers enhanced immune responses and neutralizing antibodies [22], which makes it a promising vaccine candidate against Chlamydia [23]
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