Oral immunization of mice with recombinant Lactococcus lactis expressing Cu,Zn superoxide dismutase of Brucella abortus triggers protective immunity

Sáez, Darwin; Grandón, Pamela; Rivera, Alejandra; Andrews, Edilia; Oñate, Ángel

doi:10.1016/j.vaccine.2011.12.088

Cited by 43 publications

(35 citation statements)

References 68 publications

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“…Criteria for inclusion in this study are detailed in Fig 1. A total of 117 publications that met the criteria were selected for inclusion in this study [14, 17, 18, 20–28, 32, 33, 38, 40–141]. Therefore, a total of 782 individual experiments were analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…Several Brucella proteins have been used as immunogens for experimental subunit vaccine formulations, including outer membrane proteins, namely Omp16, Omp19, Omp31, Omp28, and Omp25 [21–24], ribosomal protein L7/L12 [17,25], Cu-Zn superoxide dismutase [26], a cytoplasmic protein p39 [27], lumazine synthase BLS [28], among others. In addition, experimental DNA vaccines [28,29] as well as vectored vaccines using deliver vectors such as Salmonella enterica serotype Typhimurium [30], Escherichia coli [31], Yersinia enterocolitica [32], Lactococcus lactis [33], and the influenza virus [34] have been increasingly studied. Overexpression of Brucella antigens in attenuated vaccine strains have also been experimentally evaluated [35].…”

Section: Introductionmentioning

confidence: 99%

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Meta-Analysis and Advancement of Brucellosis Vaccinology

et al. 2016

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Background/ObjectivesIn spite of all the research effort for developing new vaccines against brucellosis, it remains unclear whether these new vaccine technologies will in fact become widely used. The goal of this study was to perform a meta-analysis to identify parameters that influence vaccine efficacy as well as a descriptive analysis on how the field of Brucella vaccinology is advancing concerning type of vaccine, improvement of protection on animal models over time, and factors that may affect protection in the mouse model.MethodsA total of 117 publications that met the criteria were selected for inclusion in this study, with a total of 782 individual experiments analyzed.ResultsAttenuated (n = 221), inactivated (n = 66) and mutant (n = 102) vaccines provided median protection index above 2, whereas subunit (n = 287), DNA (n = 68), and vectored (n = 38) vaccines provided protection indexes lower than 2. When all categories of experimental vaccines are analyzed together, the trend line clearly demonstrates that there was no improvement of the protection indexes over the past 30 years, with a low negative and non significant linear coefficient. A meta-regression model was developed including all vaccine categories (attenuated, DNA, inactivated, mutant, subunit, and vectored) considering the protection index as a dependent variable and the other parameters (mouse strain, route of vaccination, number of vaccinations, use of adjuvant, challenge Brucella species) as independent variables. Some of these variables influenced the expected protection index of experimental vaccines against Brucella spp. in the mouse model.ConclusionIn spite of the large number of publication over the past 30 years, our results indicate that there is not clear trend to improve the protective potential of these experimental vaccines.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Meta-Analysis and Advancement of Brucellosis Vaccinology

et al. 2016

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“…The use of pili as a platform to express foreign protein has several advantages for the purpose of eliciting high levels of cellular and humoral immunity: a) Each bacterial cell has numerous pili on its surface, allowing high levels of antigen expression per cell b) pili can activate the innate immune system and thus serve as an adjuvant for the induction of strong cellular and humoral immunity (13) c) expression of an antigen fused to the tip of the pilus allows B cells to recognize the antigen directly and more efficiently relative to intracellular expression (39) d) and pili may increase bacterial adhesion to the intestinal mucosa resulting in better retention of the bacteria in the gut. A previous study used recombinant L. lactis expressing HIV envelope protein (gp120) on the cell wall as an oral vaccine (11).…”

Section: Discussionmentioning

confidence: 99%

“…The key advantages of using a Lactococcus vaccine vector are: 1) Lactococcus is a GRAS (Generally Regarded As Safe) organism, 2) it naturally withstands stomach acids and bile (12), 3) it can be administered repeatedly since it survives only temporarily in the intestinal tract and does not colonize humans (12), 4) it has intrinsic adjuvant properties (13), 5) it does not require a cold chain, and 6) it is inexpensive to produce. Also Lactococcus is a Gram-positive bacterium and therefore does not possess endotoxic lipopolysaccharides (LPS), which are associated with commonly used vaccine strain Gram-negative bacteria such as Escherichia coli and Salmonella typhimurium (10, 14-17).…”

Section: Introductionmentioning

confidence: 99%

Oral Immunization with a Recombinant Lactococcus lactis–Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut

Chamcha

Jones

Quigley

et al. 2015

The Journal of Immunology

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The induction of a potent humoral and cellular immune response in mucosal tissue is important for the development of an effective HIV vaccine. Most of the current HIV vaccines under development use the intramuscular route for immunization, which is relatively poor in generating potent and long-lived mucosal immune responses. Here, we explore the ability of an oral vaccination with a probiotic organism, Lactococcus lactis (L. lactis), to elicit HIV-specific immune responses in the mucosal and systemic compartments of BALB/c mice. We expressed the HIV-1 Gag-p24 on the tip of the T3 pilus of Streptococcus pyogenes as a fusion to the Cpa protein (LL-Gag). Following four monthly LL-Gag oral immunizations we observed strong Gag-specific IgG and IgA responses in serum, feces, and vaginal secretions. However, the Gag-specific CD8 T cell responses in the blood were at or below our detection limit. Following an intramuscular modified vaccinia Ankara (MVA)/Gag boost, we observed a robust Gag-specific CD8 T cell responses both in systemic and mucosal tissue, including intraepithelial and lamina propria lymphocytes of the small intestine, Peyer's patches, and mesenteric lymph nodes. Consistent with strong immunogenicity, the LL-Gag induced activation of CD11c+ CD11b+ dendritic cells in the Peyer's patches after oral immunization. Our results demonstrate that oral immunization with L. lactis expressing an antigen on the tip of the Group-A streptococcus pilus serves as an excellent vaccine platform to induce strong mucosal humoral and cellular immunity against HIV.

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“…Periplasmic SOD from B. abortus, a major cause of brucellosis, was identified as a major cattle serumreactive protein that might serve as a Brucella vaccine immunogen (16,48,54). Vaccination with attenuated SOD deletion strains of B. abortus prevented abortion in cattle (115), and vaccination with BaSOD-overexpressing bacteria (116,117) or with liposome-encapsulated BaSOD or nucleic acid BaSOD vaccines (118, 119) also conferred a protective advantage. Previous efforts identified one of three tested peptide immunogens from the BaSOD sequence as protective when administered in mice (48).…”

Section: Structural Insights Differentiating Bacterial and Eukaryoticmentioning

confidence: 99%

Structural, Functional, and Immunogenic Insights on Cu,Zn Superoxide Dismutase Pathogenic Virulence Factors from Neisseria meningitidis and Brucella abortus

et al. 2015

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Bacterial pathogens Neisseria meningitidis and Brucella abortus pose threats to human and animal health worldwide, causing meningococcal disease and brucellosis, respectively. Mortality from acute N. meningitidis infections remains high despite antibiotics, and brucellosis presents alimentary and health consequences. Superoxide dismutases are master regulators of reactive oxygen and general pathogenicity factors and are therefore therapeutic targets. Cu,Zn superoxide dismutases (SODs) localized to the periplasm promote survival by detoxifying superoxide radicals generated by major host antimicrobial immune responses. We discovered that passive immunization with an antibody directed at N. meningitidis SOD (NmSOD) was protective in a mouse infection model. To define the relevant atomic details and solution assembly states of this important virulence factor, we report high-resolution and X-ray scattering analyses of NmSOD and of SOD from B. abortus (BaSOD). The NmSOD structures revealed an auxiliary tetrahedral Cu-binding site bridging the dimer interface; mutational analyses suggested that this metal site contributes to protein stability, with implications for bacterial defense mechanisms. Biochemical and structural analyses informed us about electrostatic substrate guidance, dimer assembly, and an exposed C-terminal epitope in the NmSOD dimer. In contrast, the monomeric BaSOD structure provided insights for extending immunogenic peptide epitopes derived from the protein. These collective results reveal unique contributions of SOD to pathogenic virulence, refine predictive motifs for distinguishing SOD classes, and suggest general targets for antibacterial immune responses. The identified functional contributions, motifs, and targets distinguishing bacterial and eukaryotic SOD assemblies presented here provide a foundation for efforts to develop SOD-specific inhibitors of or vaccines against these harmful pathogens. IMPORTANCEBy protecting microbes against reactive oxygen insults, SODs aid survival of many bacteria within their hosts. Despite the ubiquity and conservation of these key enzymes, notable species-specific differences relevant to pathogenesis remain undefined. To probe mechanisms that govern the functioning of Neisseria meningitidis and Brucella abortus SODs, we used X-ray structures, enzymology, modeling, and murine infection experiments. We identified virulence determinants common to the two homologs, assembly differences, and a unique metal reservoir within meningococcal SOD that stabilizes the enzyme and may provide a safeguard against copper toxicity. The insights reported here provide a rationale and a basis for SOD-specific drug design and an extension of immunogen design to target two important pathogens that continue to pose global health threats.

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Oral immunization of mice with recombinant Lactococcus lactis expressing Cu,Zn superoxide dismutase of Brucella abortus triggers protective immunity

Cited by 43 publications

References 68 publications

Meta-Analysis and Advancement of Brucellosis Vaccinology

Meta-Analysis and Advancement of Brucellosis Vaccinology

Oral Immunization with a Recombinant Lactococcus lactis–Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut

Structural, Functional, and Immunogenic Insights on Cu,Zn Superoxide Dismutase Pathogenic Virulence Factors from Neisseria meningitidis and Brucella abortus

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