The Chlamydia M278 Major Outer Membrane Peptide Encapsulated in the Poly(lactic acid)-Poly(ethylene glycol) Nanoparticulate Self-Adjuvanting Delivery System Protects Mice Against a Chlamydia muridarum Genital Tract Challenge by Stimulating Robust Systemic

SAURABH DIXIT; SHREE R. SINGH; RAJNISH SAHU; GIAMBARTOLOMEI, GUILLERMO H; RICHA VERMA; SKYLA A. DUNCAN; VIDA A. DENNIS

Frontiers in immunology

Frontiers Media S.A.

Año: 2018

1664-3224

Recently, we reported that our PPM chlamydial nanovaccine [a biodegradableco-polymeric PLA-PEG (poly(lactic acid)-poly(ethylene glycol))-encapsulated M278peptide (derived from the major outer membrane protein (MOMP) of Chlamydia)]exploits the caveolin-mediated endocytosis pathway for endosomal processing andMHC class II presentation to immune-potentiate Chlamydia-specific CD4+ T-cell immuneeffector responses. In the present study, we employed the Chlamydia muridarummouse infection model to evaluate the protective efficacy of PPM against a genitaltract challenge. Our results show that mice immunized with PPM were significantlyprotected against a homologous genital tract challenge evidently by reduced vaginalbacterial loads. Protection ofmice correlated with enhanced Chlamydia-specific adaptiveimmune responses predominated by IFN-g along with CD4+ T-cells proliferation and theirdifferentiation to CD4+ memory (CD44high CD62Lhigh) and effector (CD44high CD62Llow)T-cell phenotypes. We observed the elevation of M278- and MOMP-specific serumantibodies with high avidity in the ascending order IgG1 > IgG2b > IgG2a. A keyfinding was the elevated mucosal IgG1 and IgA antibody titers followed by an increasein MOMP-specific IgA after the challenge. The Th1/Th2 antibody titer ratios (IgG2a/IgG1and IgG2b/IgG1) revealed that PPM evoked a Th2-directed response, which skewed toa Th1-dominated antibody response after the bacterial challenge of mice. In addition,PPM immune sera neutralized the infectivity of C. muridarum in McCoy cells, suggestingthe triggering of functional neutralizing antibodies. Herein, we reveal for the first time that subcutaneous immunization with the self-adjuvanting biodegradable co-polymericPPM nanovaccine immune-potentiated robust CD4+ T cell-mediated immune effectorresponses; a mixed Th1 and Th2 antibody response and local mucosal IgA to protectmice against a chlamydial genital tract challenge.