ABSTRACT
Vaccines are critical tools for the prevention and treatment of several diseases. Adjuvants have been traditionally used to enhance immunity to vaccines and experimental antigens. In the present study, the adjuvant combination of CpG oligodeoxynucleotides (CpG ODN) and the innate defense regulator (IDR) peptide, IDRHH2, was evaluated for its ability to enhance and modulate the immune response when formulated with alum and the recombinant hepatitis B surface antigen (HBsAg). The CpGHH2 complex enhanced the secretions of tumor necrosis factorα, monocyte chemotactic protein 1 and interferonγ by human peripheral blood mononuclear cells and promoted murine bone marrow dentritic cell maturation. In addition, the present study demonstrated that IDRHH2 was chemotactic for human neutrophils, THP1 cells and RAW264.7 cells at concentrations between 2.5 and 40 µg/ml. The present study also observed that signiï¬cantly higher antiHBs antibody titers, which were sustained at high levels for as long as 35 weeks following the boost immunization, were induced by the combination adjuvant, even when coadministered with a commercial hepatitis B vaccine at a low antigen dose (0.1 µg HBsAg). Notably, the level of IgG2a was almost equal to the level of IgG1, indicating that a balanced T helper (Th)1/Th2 immune response was elicited by the novel vaccine, which was consistent with the ELISpot results. These data suggest that the CpGHH2 complex may be a potential effective adjuvant, which facilitates a reduction in the dose of antigen and induces longlasting, balanced immune responses.
Subject(s)
Adjuvants, Immunologic/administration & dosage , Immunity, Innate/immunology , Oligodeoxyribonucleotides/administration & dosage , Peptides/administration & dosage , Animals , Hepatitis B Surface Antigens/administration & dosage , Hepatitis B Surface Antigens/chemistry , Hepatitis B Vaccines/immunology , Humans , Immunity, Innate/drug effects , Leukocytes, Mononuclear/immunology , Mice , Oligodeoxyribonucleotides/immunology , Peptides/immunology , Th1 Cells/drug effects , Th1 Cells/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Multidrug-resistant bacteria are an increasingly serious threat to human and animal health. However, novel drugs that can manage infections by multidrug-resistant bacteria have proved elusive. Here we show that glucose and alanine abundances are greatly suppressed in kanamycin-resistant Edwardsiella tarda by GC-MS-based metabolomics. Exogenous alanine or glucose restores susceptibility of multidrug-resistant E. tarda to killing by kanamycin, demonstrating an approach to killing multidrug-resistant bacteria. The mechanism underlying this approach is that exogenous glucose or alanine promotes the TCA cycle by substrate activation, which in turn increases production of NADH and proton motive force and stimulates uptake of antibiotic. Similar results are obtained with other Gram-negative bacteria (Vibrio parahaemolyticus, Klebsiella pneumoniae, Pseudomonas aeruginosa) and Gram-positive bacterium (Staphylococcus aureus), and the results are also reproduced in a mouse model for urinary tract infection. This study establishes a functional metabolomics-based strategy to manage infection by antibiotic-resistant bacteria.