29 results on '"Jiménez de Bagüés MP"'
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2. The virB Operon Is Essential for Lethality of Brucella microti in the Balb/c Murine Model of Infection.
- Author
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Hanna N, Jiménez de Bagüés MP, Ouahrani-Bettache S, El Yakhlifi Z, Köhler S, and Occhialini A
- Abstract
In murine infections, Brucella microti exhibits an atypical and highly pathogenic behavior resulting in a mortality of 82%. In this study, the possible involvement of the virB type IV secretion system, a key virulence factor of Brucella sp., in this lethal phenotype was investigated. As previously described for B. suis, expression of the virB operon of B. microti was induced in acid minimal medium, partially mimicking intracellular environment. Early neutralization of cellular compartments abolished intracellular replication of B. microti, showing that acidity of the Brucella-containing vacuole is an essential trigger. A [Delta]virB mutant of B. microti exhibited strong attenuation in murine and human macrophages in vitro. Interestingly, infection with this mutant was not lethal in Balb/c mice and lacked the typical intrasplenic peak at 3 days post-infection, hence demonstrating that lethality of B. microti in murine infection absolutely requires a functional virB operon. [ABSTRACT FROM AUTHOR]
- Published
- 2011
3. Lethality of Brucella microti in a murine model of infection depends on the wbkE gene involved in O-polysaccharide synthesis.
- Author
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Ouahrani-Bettache S, Jiménez De Bagüés MP, De La Garza J, Freddi L, Bueso JP, Lyonnais S, Al Dahouk S, De Biase D, Köhler S, and Occhialini A
- Subjects
- Animals, Brucella enzymology, Disease Models, Animal, Female, Genotype, Macrophages microbiology, Mice, Mice, Inbred BALB C, Mutation, Phenotype, Virulence, Bacterial Proteins genetics, Brucella genetics, Brucella pathogenicity, Brucellosis microbiology, Glycosyltransferases genetics, Polysaccharides, Bacterial biosynthesis
- Abstract
Brucella microti was isolated a decade ago from wildlife and soil in Europe. Compared to the classical Brucella species, it exhibits atypical virulence properties such as increased growth in human and murine macrophages and lethality in experimentally infected mice. A spontaneous rough (R) mutant strain, derived from the smooth reference strain CCM4915
T , showed increased macrophage colonization and was non-lethal in murine infections. Whole-genome sequencing and construction of an isogenic mutant of B. microti and Brucella suis 1330 revealed that the R-phenotype was due to a deletion in a single gene, namely wbkE (BMI_I539), encoding a putative glycosyltransferase involved in lipopolysaccharide (LPS) O-polysaccharide biosynthesis. Complementation of the R-strains with the wbkE gene restored the smooth phenotype and the ability of B. microti to kill infected mice. LPS with an intact O-polysaccharide is therefore essential for lethal B. microti infections in the murine model, demonstrating its importance in pathogenesis.- Published
- 2019
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4. Concomitant Temperature Stress and Immune Activation may Increase Mortality Despite Efficient Clearance of an Intracellular Bacterial Infection in Atlantic Cod.
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Larsen AK, Nymo IH, Sørensen KK, Seppola M, Rødven R, Jiménez de Bagüés MP, Al Dahouk S, and Godfroid J
- Abstract
The environmental temperature has profound effects on biological systems of marine aquatic organisms and plays a critical role in species distribution and abundance. Particularly during the warmer seasons, variations in habitat temperature may introduce episodes of stressful temperatures which the organisms must adapt to and compensate for to maintain physiological homeostasis. The marine environment is changing and predicted raises in water temperatures will affect numerous marine species. Translocation of pathogens follow migration of species and alternations in physical environmental parameters may have influence upon the virulence of pathogens, as well as the hosts immune responses. While pathogenicity of many true pathogens is expected to increase following climate induced temperature stress, the impact from environmental stressors on the occurrence and severity of opportunistic infections is unknown. Here we describe how thermal stress in the cold-water species Atlantic cod influenced the fish immune responses against an opportunistic intracellular bacterium. Following experimental infection with Brucella pinnipedialis at normal water temperature (6°C) and sub-optimal temperature (15°C), cod cleared the intracellular bacteria more rapidly at the highest temperature. The overall immune response was faster and of higher amplitude at 15°C, however, a significant number of cod died at this temperature despite efficient clearance of infection. An increased growth rate not affected by infection was observed at 15°C, confirming multiple energy demanding processes taking place. Serum chemistry suggested that general homeostasis was influenced by both infection and increased water temperature, highlighting the cumulative stress responses (allostatic load) generated by simultaneous stressors. Our results suggest a trade-off between resistance and tolerance to survive infection at sub-optimal temperatures and raise questions concerning the impact of increased water temperatures on the energetic costs of immune system activation in aquatic ectotherms.
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- 2018
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5. RegA Plays a Key Role in Oxygen-Dependent Establishment of Persistence and in Isocitrate Lyase Activity, a Critical Determinant of In vivo Brucella suis Pathogenicity.
- Author
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Abdou E, Jiménez de Bagüés MP, Martínez-Abadía I, Ouahrani-Bettache S, Pantesco V, Occhialini A, Al Dahouk S, Köhler S, and Jubier-Maurin V
- Subjects
- Adaptation, Physiological, Animals, Base Sequence, Brucella suis growth & development, Brucella suis pathogenicity, Brucellosis metabolism, Brucellosis microbiology, DNA, Bacterial, Disease Models, Animal, Down-Regulation, Energy Metabolism, Female, Genes, Bacterial genetics, Isocitrate Lyase metabolism, Metabolic Networks and Pathways genetics, Mice, Mice, Inbred BALB C, Mutation, Nitrite Reductases analysis, Oxidoreductases analysis, Oxygen metabolism, Oxygen Consumption physiology, Proteome analysis, RNA, Bacterial isolation & purification, Up-Regulation, Virulence genetics, Bacterial Proteins genetics, Bacterial Proteins physiology, Brucella suis genetics, Brucella suis metabolism, Gene Expression Regulation, Bacterial genetics, Hypoxia metabolism, Isocitrate Lyase genetics, Regulon genetics
- Abstract
For aerobic human pathogens, adaptation to hypoxia is a critical factor for the establishment of persistent infections, as oxygen availability is low inside the host. The two-component system RegB/A of Brucella suis plays a central role in the control of respiratory systems adapted to oxygen deficiency, and in persistence in vivo . Using an original " in vitro model of persistence" consisting in gradual oxygen depletion, we compared transcriptomes and proteomes of wild-type and Δ regA strains to identify the RegA-regulon potentially involved in the set-up of persistence. Consecutive to oxygen consumption resulting in growth arrest, 12% of the genes in B. suis were potentially controlled directly or indirectly by RegA, among which numerous transcriptional regulators were up-regulated. In contrast, genes or proteins involved in envelope biogenesis and in cellular division were repressed, suggesting a possible role for RegA in the set-up of a non-proliferative persistence state. Importantly, the greatest number of the RegA-repressed genes and proteins, including aceA encoding the functional IsoCitrate Lyase (ICL), were involved in energy production. A potential consequence of this RegA impact may be the slowing-down of the central metabolism as B. suis progressively enters into persistence. Moreover, ICL is an essential determinant of pathogenesis and long-term interactions with the host, as demonstrated by the strict dependence of B. suis on ICL activity for multiplication and persistence during in vivo infection. RegA regulates gene or protein expression of all functional groups, which is why RegA is a key regulator of B. suis in adaptation to oxygen depletion. This function may contribute to the constraint of bacterial growth, typical of chronic infection. Oxygen-dependent activation of two-component systems that control persistence regulons, shared by several aerobic human pathogens, has not been studied in Brucella sp. before. This work therefore contributes significantly to the unraveling of persistence mechanisms in this important zoonotic pathogen.
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- 2017
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6. Brucella spp. of amphibians comprise genomically diverse motile strains competent for replication in macrophages and survival in mammalian hosts.
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Al Dahouk S, Köhler S, Occhialini A, Jiménez de Bagüés MP, Hammerl JA, Eisenberg T, Vergnaud G, Cloeckaert A, Zygmunt MS, Whatmore AM, Melzer F, Drees KP, Foster JT, Wattam AR, and Scholz HC
- Subjects
- Animals, Animals, Zoo, Anura, Bacterial Proteins metabolism, Biological Evolution, Brucellaceae classification, Brucellaceae growth & development, Brucellaceae metabolism, Cell Line, Flagella genetics, Flagella metabolism, Flagella ultrastructure, Genetic Heterogeneity, Germany, Gram-Negative Bacterial Infections microbiology, Liver microbiology, Macrophages microbiology, Mice, Mice, Inbred BALB C, Multilocus Sequence Typing, Spleen microbiology, Tanzania, Bacterial Proteins genetics, Brucellaceae genetics, Gene Expression Regulation, Bacterial, Gram-Negative Bacterial Infections veterinary, Host-Pathogen Interactions, Phylogeny
- Abstract
Twenty-one small Gram-negative motile coccobacilli were isolated from 15 systemically diseased African bullfrogs (Pyxicephalus edulis), and were initially identified as Ochrobactrum anthropi by standard microbiological identification systems. Phylogenetic reconstructions using combined molecular analyses and comparative whole genome analysis of the most diverse of the bullfrog strains verified affiliation with the genus Brucella and placed the isolates in a cluster containing B. inopinata and the other non-classical Brucella species but also revealed significant genetic differences within the group. Four representative but molecularly and phenotypically diverse strains were used for in vitro and in vivo infection experiments. All readily multiplied in macrophage-like murine J774-cells, and their overall intramacrophagic growth rate was comparable to that of B. inopinata BO1 and slightly higher than that of B. microti CCM 4915. In the BALB/c murine model of infection these strains replicated in both spleen and liver, but were less efficient than B. suis 1330. Some strains survived in the mammalian host for up to 12 weeks. The heterogeneity of these novel strains hampers a single species description but their phenotypic and genetic features suggest that they represent an evolutionary link between a soil-associated ancestor and the mammalian host-adapted pathogenic Brucella species.
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- 2017
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7. Toll-Like Receptors 2 and 4 Cooperate in the Control of the Emerging Pathogen Brucella microti .
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Arias MA, Santiago L, Costas-Ramon S, Jaime-Sánchez P, Freudenberg M, Jiménez De Bagüés MP, and Pardo J
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- Animals, Brucellosis immunology, Brucellosis microbiology, Brucellosis pathology, Dendritic Cells immunology, Liver microbiology, Mice, Mice, Knockout, Spleen microbiology, T-Lymphocytes, Cytotoxic immunology, Brucella immunology, Brucellosis veterinary, Rodent Diseases immunology, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 metabolism
- Abstract
Toll-like receptors (TLRs) recognize pathogen-derived molecules and play a critical role during the host innate and adaptive immune response. Brucella spp. are intracellular gram-negative bacteria including several virulent species, which cause a chronic zoonotic infection in a wide range of mammalian hosts known as brucellosis. A new Brucella species, Brucella microti , was recently isolated from wild rodents and found to be highly pathogenic in mice. Using this species-specific model, it was previously found that CD8
+ T cells are required to control this infection. In order to find out the role of TLR-mediated responses in the control of this pathogen, the course of infection of B. microti was analyzed over 3 weeks in wild-type (WT) and TLR knock out (KO) mice including TLR2-/- , TLR4-/- , TLR9-/- , TLR2×4-/- and TLR2×4×9-/- . WT and single TLR2, TLR4 and TLR9 KO mice similarly control infection in liver and spleen. In contrast, bacterial clearance was delayed in TLR2×4-/- and TLR2×4×9-/- mice at 7 and 14 days post-infection. This defect correlated with impaired maturation and pro-inflammatory cytokine production in B. microti -infected dendritic cells from TLR2×4-/- and TLR2×4×9-/- mice. Finally, it was found that Tc cells from TLR2×4-/- and TLR2×4×9-/- mice showed reduced ability to inhibit growth of B. microti in macrophages, suggesting the involvement of TLR2 and 4 in the generation of specific Tc cells. Our findings indicate that TLR2 and TLR4 are required to control B. microti infection in mice and that this effect could be related to its participation in the maturation of dendritic cells and the generation of specific CD8+ Tc cells.- Published
- 2017
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8. Experimental Challenge of Atlantic Cod (Gadus morhua) with a Brucella pinnipedialis Strain from Hooded Seal (Cystophora cristata).
- Author
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Nymo IH, Seppola M, Al Dahouk S, Bakkemo KR, Jiménez de Bagüés MP, Godfroid J, and Larsen AK
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- Animals, Bacteremia microbiology, Bacteremia veterinary, Bacterial Load veterinary, Brucellosis microbiology, Brucellosis transmission, Feces microbiology, Female, Fish Diseases microbiology, Heart microbiology, Kidney microbiology, Liver microbiology, Muscle, Skeletal microbiology, Ovary microbiology, Brucella pathogenicity, Brucellosis veterinary, Gadus morhua microbiology, Seals, Earless microbiology
- Abstract
Pathology has not been observed in true seals infected with Brucella pinnipedialis. A lack of intracellular survival and multiplication of B. pinnipedialis in hooded seal (Cystophora cristata) macrophages in vitro indicates a lack of chronic infection in hooded seals. Both epidemiology and bacteriological patterns in the hooded seal point to a transient infection of environmental origin, possibly through the food chain. To analyse the potential role of fish in the transmission of B. pinnipedialis, Atlantic cod (Gadus morhua) were injected intraperitoneally with 7.5 x 107 bacteria of a hooded seal field isolate. Samples of blood, liver, spleen, muscle, heart, head kidney, female gonads and feces were collected on days 1, 7, 14 and 28 post infection to assess the bacterial load, and to determine the expression of immune genes and the specific antibody response. Challenged fish showed an extended period of bacteremia through day 14 and viable bacteria were observed in all organs sampled, except muscle, until day 28. Neither gross lesions nor mortality were recorded. Anti-Brucella antibodies were detected from day 14 onwards and the expression of hepcidin, cathelicidin, interleukin (IL)-1β, IL-10, and interferon (IFN)-γ genes were significantly increased in spleen at day 1 and 28. Primary mononuclear cells isolated from head kidneys of Atlantic cod were exposed to B. pinnipedialis reference (NCTC 12890) and hooded seal (17a-1) strain. Both bacterial strains invaded mononuclear cells and survived intracellularly without any major reduction in bacterial counts for at least 48 hours. Our study shows that the B. pinnipedialis strain isolated from hooded seal survives in Atlantic cod, and suggests that Atlantic cod could play a role in the transmission of B. pinnipedialis to hooded seals in the wild.
- Published
- 2016
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9. Marine Mammal Brucella Reference Strains Are Attenuated in a BALB/c Mouse Model.
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Nymo IH, Arias MA, Pardo J, Álvarez MP, Alcaraz A, Godfroid J, and Jiménez de Bagüés MP
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- Animals, Cytokines metabolism, Female, Mice, Mice, Inbred BALB C, Organ Size physiology, Spleen metabolism, Brucella pathogenicity, Brucellosis microbiology
- Abstract
Brucellosis is a zoonosis of worldwide distribution with numerous animal host species. Since the novel isolation of Brucella spp. from marine mammals in 1994 the bacteria have been isolated from various marine mammal hosts. The marine mammal reference strains Brucella pinnipedialis 12890 (harbour seal, Phoca vitulina) and Brucella ceti 12891 (harbour porpoise, Phocoena phocoena) were included in genus Brucella in 2007, however, their pathogenicity in the mouse model is pending. Herein this is evaluated in BALB/c mice with Brucella suis 1330 as a control. Both marine mammal strains were attenuated, however, B. ceti was present at higher levels than B. pinnipedialis in blood, spleen and liver throughout the infection, in addition B. suis and B. ceti were isolated from brains and faeces at times with high levels of bacteraemia. In B. suis-infected mice serum cytokines peaked at day 7. In B. pinnipedialis-infected mice, levels were similar, but peaked predominantly at day 3 and an earlier peak in spleen weight likewise implied an earlier response. The inflammatory response induced pathology in the spleen and liver. In B. ceti-infected mice, most serum cytokine levels were comparable to those in uninfected mice, consistent with a limited inflammatory response, which also was indicated by restricted spleen and liver pathology. Specific immune responses against all three strains were detected in vitro after stimulation of splenocytes from infected mice with the homologous heat-killed brucellae. Antibody responses in vivo were also induced by the three brucellae. The immunological pattern of B. ceti in combination with persistence in organs and limited pathology has heretofore not been described for other brucellae. These two marine mammal wildtype strains show an attenuated pattern in BALB/c mice only previously described for Brucella neotomea.
- Published
- 2016
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10. The new strains Brucella inopinata BO1 and Brucella species 83-210 behave biologically like classic infectious Brucella species and cause death in murine models of infection.
- Author
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Jiménez de Bagüés MP, Iturralde M, Arias MA, Pardo J, Cloeckaert A, and Zygmunt MS
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- Animals, Cells, Cultured, Macrophages microbiology, Mice, Mice, Inbred Strains, Virulence, Brucella classification, Brucella pathogenicity, Brucellosis microbiology, Brucellosis mortality
- Abstract
Background: Recently, novel atypical Brucella strains isolated from humans and wild rodents have been reported. They are phenotypically close to Ochrobactrum species but belong to the genus Brucella, based on genetic relatedness, although genetic diversity is higher among the atypical Brucella strains than between the classic species. They were classified within or close to the novel species Brucella inopinata. However, with the exception of Brucella microti, the virulence of these novel strains has not been investigated in experimental models of infection., Methods: The type species B. inopinata strain BO1 (isolated from a human) and Brucella species strain 83-210 (isolated from a wild Australian rodent) were investigated. A classic infectious Brucella reference strain, B. suis 1330, was also used. BALB/c, C57BL/6, and CD1 mice models and C57BL/6 mouse bone-marrow-derived macrophages (BMDMs) were used as infection models., Results: Strains BO1 and 83-210 behaved similarly to reference strain 1330 in all mouse infection models: there were similar growth curves in spleens and livers of mice and similar intracellular replication rates in BMDMs. However, unlike strain 1330, strains BO1 and 83-210 showed lethality in the 3 mouse models., Conclusions: The novel atypical Brucella strains of this study behave like classic intracellular Brucella pathogens. In addition, they cause death in murine models of infection, as previously published for B. microti, another recently described environmental and wildlife species., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2014
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11. RegA, the regulator of the two-component system RegB/RegA of Brucella suis, is a controller of both oxidative respiration and denitrification required for chronic infection in mice.
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Abdou E, Deredjian A, Jiménez de Bagüés MP, Köhler S, and Jubier-Maurin V
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- Adaptation, Physiological, Animals, Bacterial Proteins genetics, Brucella suis genetics, Chronic Disease, Denitrification, Gene Expression Regulation, Enzymologic, Mice, Mice, Inbred BALB C, Nitrite Reductases genetics, Nitrite Reductases metabolism, Oxidoreductases genetics, Oxidoreductases metabolism, Oxygen metabolism, Bacterial Proteins metabolism, Brucella suis metabolism, Brucellosis microbiology, Gene Expression Regulation, Bacterial physiology, Oxygen Consumption physiology
- Abstract
Adaptation to oxygen deficiency is essential for virulence and persistence of Brucella inside the host. The flexibility of this bacterium with respect to oxygen depletion is remarkable, since Brucella suis can use an oxygen-dependent transcriptional regulator of the FnrN family, two high-oxygen-affinity terminal oxidases, and a complete denitrification pathway to resist various conditions of oxygen deficiency. Moreover, our previous results suggested that oxidative respiration and denitrification can be simultaneously used by B. suis under microaerobiosis. The requirement of a functional cytochrome bd ubiquinol oxidase for nitrite reductase expression evidenced the linkage of these two pathways, and the central role of the two-component system RegB/RegA in the coordinated control of both respiratory systems was demonstrated. We propose a scheme for global regulation of B. suis respiratory pathways by the transcriptional regulator RegA, which postulates a role for the cytochrome bd ubiquinol oxidase in redox signal transmission to the histidine sensor kinase RegB. More importantly, RegA was found to be essential for B. suis persistence in vivo within oxygen-limited target organs. It is conceivable that RegA acts as a controller of numerous systems involved in the establishment of the persistent state, characteristic of chronic infections by Brucella.
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- 2013
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12. The glutamic acid decarboxylase system of the new species Brucella microti contributes to its acid resistance and to oral infection of mice.
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Occhialini A, Jiménez de Bagüés MP, Saadeh B, Bastianelli D, Hanna N, De Biase D, and Köhler S
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- Acids toxicity, Animals, Brucella genetics, Disease Models, Animal, Escherichia coli enzymology, Escherichia coli genetics, Female, Gene Deletion, Genetic Complementation Test, Glutamate Decarboxylase genetics, Mice, Mice, Inbred BALB C, Virulence Factors genetics, Acids metabolism, Brucella enzymology, Brucella pathogenicity, Brucellosis microbiology, Glutamate Decarboxylase metabolism, Stress, Physiological, Virulence Factors metabolism
- Abstract
Background: Genome analysis indicated that the new species Brucella microti possesses a potentially functional glutamate decarboxylase (GAD) system involved in extreme acid resistance in several foodborne bacteria. The contribution of this system in adaptation of B. microti to an acidic environment, including the intracellular vacuole and stomach, was investigated., Results: B. microti was GAD positive and able to export its product, γ-aminobutyrate, to the extracellular medium. The resistance of B. microti to acid stress (pH 2.5) was glutamate dependent. Mutants affected in the GAD system lost this resistance, demonstrating its direct involvement in survival under these conditions. The reciprocal heterologous complementation of mutants with the GAD systems of Escherichia coli or B. microti confirmed conserved functions in both bacterial species. A gad mutant was not attenuated during infection of macrophages, where Brucella resides in an acidified vacuole at a pH of 4-4.5 during the early phase of macrophage infection, but GAD contributed to the survival of B. microti in a murine model following oral infection., Conclusions: This work provides first evidence that the GAD system might play an essential role in the resistance of an environment-borne, pathogenic Brucella species to extreme acid shock and during passage through the host stomach following oral infection.
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- 2012
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13. Course of infection with the emergent pathogen Brucella microti in immunocompromised mice.
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Jiménez de Bagüés MP, de Martino A, Quintana JF, Alcaraz A, and Pardo J
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- Animals, B-Lymphocytes immunology, Bacterial Load, Brucella classification, Brucella immunology, Brucellosis microbiology, Disease Models, Animal, Female, Humans, Killer Cells, Natural immunology, Liver immunology, Liver microbiology, Liver pathology, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, SCID, Species Specificity, Spleen immunology, Spleen microbiology, Spleen pathology, T-Lymphocytes immunology, Brucella pathogenicity, Brucellosis immunology, Immunocompromised Host
- Abstract
A new Brucella species, Brucella microti, has been isolated from wild rodents and found to be pathogenic in mice. The biological relevance of this new mouse pathogen is clear, as it allows us to study Brucella infection in a species-specific model. The course of infection in wild-type (wt) and immunodeficient mice that lack B (Jh), T and B (SCID), or T, B, and NK (SCID.Beige) cells was analyzed over 3 weeks. wt mice completely cleared bacteria from the liver and spleen after that time. However, SCID mice showed a much higher bacterial load in the spleen and liver than wt and Jh mice after 1 week and maintained the same level during the next 2 weeks. All mice tested survived for the 3 weeks. In contrast, the bacterial levels in mice that lacked NK cell activity progressively increased and these mice succumbed to infection after 16 to 18 days. Histopathology analysis of infected mice showed extensive areas of necrotic tissue and thrombosis in liver after 1 week in all infected SCID.Beige mice but were not seen in either SCID or wt animals. These processes were dramatically increased after 21 days, corresponding with the death of SCID.Beige animals. Our results indicate that T and/or B cells are required for the control of infection with the mouse pathogen Brucella microti in liver and spleen but that NK cells are crucial for survival in the absence of B and T cells. In addition, they suggest that controlled granuloma formation is critical to clear this type of infection in wt mice.
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- 2011
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14. The new species Brucella microti replicates in macrophages and causes death in murine models of infection.
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Jiménez de Bagüés MP, Ouahrani-Bettache S, Quintana JF, Mitjana O, Hanna N, Bessoles S, Sanchez F, Scholz HC, Lafont V, Köhler S, and Occhialini A
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- Animals, Brucellosis immunology, Brucellosis mortality, Humans, Liver pathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Organ Size, Spleen pathology, Brucella classification, Brucella physiology, Brucellosis microbiology, Macrophages microbiology
- Abstract
Background: The recent isolation of Brucella microti from the common vole, the red fox, and the soil raises the possibility of an eventual reemergence of brucellosis in Europe. In this work, the pathogenic potential of this new Brucella species in both in vitro and in vivo models of infection was analyzed., Methods: The ability of B. microti (as compared to that of the closely related species Brucella suis) to replicate in human macrophages and in human and murine macrophage-like cells was determined. The behavior of B. microti and B. suis was evaluated in vivo in murine models of infection with Balb/c, CD1, and C57BL/6 mice., Results: B. microti showed an enhanced capacity for intramacrophagic replication compared with that of B. suis. Surprisingly, and in contrast to other species of Brucella, 10(5) colony-forming units of B. microti killed 82% of Balb/c mice within 7 days. Infection of spleen and liver with B. microti peaked at day 3, compared with B. suis infection, which peaked at day 7. Sublethal doses of B. microti induced good protection against a subsequent challenge with lethal doses., Conclusions: In experimental cellular and murine infections, B. microti exhibited a high pathogenic potential, compared with other Brucella species.
- Published
- 2010
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15. Different roles of the two high-oxygen-affinity terminal oxidases of Brucella suis: Cytochrome c oxidase, but not ubiquinol oxidase, is required for persistence in mice.
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Jiménez de Bagüés MP, Loisel-Meyer S, Liautard JP, and Jubier-Maurin V
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- Animals, Brucella suis enzymology, Disease Models, Animal, Macrophages microbiology, Mice, Mice, Inbred BALB C, Brucella suis pathogenicity, Brucellosis enzymology, Electron Transport Complex IV metabolism, Oxidoreductases metabolism
- Abstract
The survival of Brucella suis mutant strains in mice demonstrated different roles of the two high-oxygen-affinity terminal oxidases. The cbb3-type cytochrome c oxidase was essential for chronic infection in oxygen-deficient organs. Lack of the cytochrome bd ubiquinol oxidase led to hypervirulence of bacteria, which could rely on nitrite accumulation inhibiting the inducible nitric oxide synthase of the host.
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- 2007
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16. Requirement of norD for Brucella suis virulence in a murine model of in vitro and in vivo infection.
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Loisel-Meyer S, Jiménez de Bagüés MP, Bassères E, Dornand J, Köhler S, Liautard JP, and Jubier-Maurin V
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- Animals, Brucella suis genetics, Disease Models, Animal, Mice, Nitric Oxide biosynthesis, Oxidoreductases genetics, Brucella suis pathogenicity, Brucellosis microbiology, Macrophages microbiology, Oxidoreductases physiology, Virulence physiology
- Abstract
A mutant of Brucella suis bearing a Tn5 insertion in norD, the last gene of the operon norEFCBQD, encoding nitric oxide reductase, was unable to survive under anaerobic denitrifying conditions. The norD strain exhibited attenuated multiplication within nitric oxide-producing murine macrophages and rapid elimination in mice, hence demonstrating that norD is essential for Brucella virulence.
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- 2006
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17. Differential use of the two high-oxygen-affinity terminal oxidases of Brucella suis for in vitro and intramacrophagic multiplication.
- Author
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Loisel-Meyer S, Jiménez de Bagüés MP, Köhler S, Liautard JP, and Jubier-Maurin V
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- Aerobiosis, Bacterial Proteins genetics, Bacterial Proteins metabolism, Brucella suis genetics, Cell Line, Cell Proliferation, Electron Transport Complex IV genetics, Electron Transport Complex IV metabolism, Gene Expression Regulation, Bacterial, Humans, Macrophages metabolism, Oxidoreductases genetics, Transcription, Genetic, Brucella suis enzymology, Brucella suis growth & development, Macrophages microbiology, Oxidoreductases metabolism, Oxygen metabolism
- Abstract
Expression of the high-oxygen-affinity cytochrome cbb3 and cytochrome bd ubiquinol oxidases of Brucella suis was studied in vitro and in the intramacrophagic niche, which was previously proposed to be oxygen limited. The cytochrome cbb3 oxidase was exclusively expressed in vitro, whereas the cytochrome bd oxidase was preferentially used inside macrophages and contributed to intracellular bacterial replication.
- Published
- 2005
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18. Analysis of the behavior of eryC mutants of Brucella suis attenuated in macrophages.
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Burkhardt S, Jiménez de Bagüés MP, Liautard JP, and Köhler S
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- Animals, Brucella suis genetics, Brucella suis growth & development, Gene Deletion, Mice, Mice, Inbred BALB C, Mutation, Spleen microbiology, Virulence genetics, Bacterial Proteins genetics, Brucella suis pathogenicity, Erythritol metabolism, Macrophages microbiology, Sugar Alcohol Dehydrogenases genetics
- Abstract
The facultatively intracellular pathogen Brucella, characterized by its capacity to replicate in professional and non professional phagocytes, also causes abortion in ruminants. This property has been linked to the presence of erythritol in the placenta, as brucellae preferentially utilize erythritol. The ery operon encodes enzymes involved in erythritol metabolism, and a link with virulence has since been discussed. Allelic exchange mutants in eryC of Brucella suis were erythritol sensitive in vitro with a MIC of 1 to 5 mM of erythritol. Their multiplication in macrophage-like cells was 50- to 90-fold reduced, but complementation of the mutant restored wild-type levels of intracellular multiplication and the capacity to use erythritol as a sole carbon source. In vivo, the eryC mutant colonized the spleens of infected BALB/c mice to a significantly lower extent than the wild type and the complemented strain. Interestingly, eryC mutants that were in addition spontaneously erythritol tolerant nevertheless exhibited wild-type-like intramacrophagic and intramurine replication. We concluded from our results that erythritol was not an essential carbon source for the pathogen in the macrophage host cell but that the inactivation of the eryC gene significantly reduced the intramacrophagic and intramurine fitness of B. suis.
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- 2005
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19. Regulation of the mitogen-activated protein kinases by Brucella spp. expressing a smooth and rough phenotype: relationship to pathogen invasiveness.
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Jiménez de Bagüés MP, Gross A, Terraza A, and Dornand J
- Subjects
- Animals, Brucella classification, Brucellosis microbiology, Cell Line, Lipopolysaccharides pharmacology, Macrophage Activation, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Phenotype, Virulence, p38 Mitogen-Activated Protein Kinases metabolism, Brucella growth & development, Brucella pathogenicity, Enzyme Activation, Gene Expression Regulation, Macrophages microbiology, Mitogen-Activated Protein Kinases metabolism
- Abstract
By comparing smooth wild-type Brucella spp. to their rough mutants, we show that the LPS O chain restricted the activation of the ERK1/2 and p38 mitogen-activated protein kinase (MAPK) pathways, thus preventing the synthesis of immune mediators that regulate host defense. We conclude that the MAPKs are a target for immune intervention by virulent smooth Brucella.
- Published
- 2005
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20. Different responses of macrophages to smooth and rough Brucella spp.: relationship to virulence.
- Author
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Jiménez de Bagüés MP, Terraza A, Gross A, and Dornand J
- Subjects
- Animals, Brucella melitensis classification, Brucella melitensis genetics, Brucella suis classification, Brucella suis genetics, Brucellosis immunology, Brucellosis microbiology, Cell Line, Lipopolysaccharides immunology, Macrophage Activation, Mice, Mutation, Nitric Oxide metabolism, Tumor Necrosis Factor-alpha metabolism, Virulence, Brucella melitensis pathogenicity, Brucella suis pathogenicity, Macrophages immunology, Macrophages microbiology
- Abstract
By comparing smooth wild-type Brucella strains to their rough mutants, we show that the lipopolysaccharide (LPS) O side chain of pathogenic Brucella has a dramatic impact on macrophage activation. It favors the development of virulent Brucella by preventing the synthesis of immune mediators, important for host defense. We conclude that this O chain property is firmly linked to Brucella virulence.
- Published
- 2004
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- View/download PDF
21. The defect in the metabolism of erythritol of the Brucella abortus B19 vaccine strain is unrelated with its attenuated virulence in mice.
- Author
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Sangari FJ, Grilló MJ, Jiménez De Bagüés MP, González-Carreró MI, García-Lobo JM, Blasco JM, and Agüero J
- Subjects
- Animals, Brucella abortus growth & development, Brucella abortus pathogenicity, Female, Mice, Mice, Inbred BALB C, Oxidation-Reduction, Phenotype, Virulence, Brucella abortus metabolism, Erythritol metabolism
- Abstract
The role of the defect in erythritol catabolism in the attenuated virulence of Brucella abortus B19 vaccine strain in mice was investigated by means of five different strains: (i) the erythritol sensitive B19 vaccine strain; (ii) a natural erythritol tolerant (NET) mutant obtained spontaneously from B19; (iii) an erythritol resistant derivative from B19 (FJS19) obtained by gene replacement of the deleted ery region; (iv) the erythritol resistant B. abortus 2308 reference virulent strain; and (v) an erythritol sensitive mutant (227 strain) obtained from strain 2308 by transposon insertion in the chromosomal ery region. Besides virulence for mice, erythritol oxidation as well as other phenotypic markers were tested in all the strains. The 2308 and FJS19 strains grew in the presence of erythritol and oxidized the sugar, whereas the B19 and 227 strains did not. The NET strain grew in presence of erythritol but was unable to oxidize it. The B19 vaccine strain and its two erythritol resistant derivatives, NET and FJS19, showed similar residual virulence and splenic time courses in mice. Moreover, the virulent strain 2308 and its erythritol sensitive derivative (227 strain) exhibited similar levels of splenic infection. Altogether, these results demonstrate that the genetic region implicated in erythritol catabolism is not related to the low virulence exhibited by B19 in mice.
- Published
- 1998
- Full Text
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22. Comparison of two selective media for the isolation of Brucella melitensis from naturally infected sheep and goats.
- Author
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Marin CM, Jiménez de Bagüés MP, Barberán M, and Blasco JM
- Subjects
- Animals, Female, Brucella melitensis isolation & purification, Culture Media, Goats microbiology, Sheep microbiology
- Abstract
The efficacy of two selective media for the isolation of Brucella melitensis from naturally infected sheep and goats was compared. Two hundred and eighty sheep and 60 goats belonging to B melitensis-infected flocks were slaughtered and samples of milk (when available) and seven tissues were taken from each animal for bacteriological analyses. A modified Thayer-Martin's medium was more sensitive than Farrell's medium; by the combined use of both media 142 infected sheep and 40 infected goats were detected, and 486 of the samples from the sheep and 179 of the samples from the goats were found to be infected.
- Published
- 1996
- Full Text
- View/download PDF
23. The Brucella abortus RB51 vaccine does not confer protection against Brucella ovis in rams.
- Author
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Jiménez de Bagüés MP, Barberán M, Marín CM, and Blasco JM
- Subjects
- Animals, Antibodies, Bacterial biosynthesis, Antibodies, Bacterial blood, Brucellosis immunology, Brucellosis prevention & control, Immunity, Innate immunology, Male, Random Allocation, Sheep, Brucella Vaccine immunology, Brucella abortus immunology, Brucellosis veterinary, Sheep Diseases immunology, Sheep Diseases prevention & control
- Abstract
The protective efficacy against Brucella ovis of the live vaccine Brucella abortus strain RB51 has been evaluated in rams using the attenuated B. melitensis strain Rev 1 as a reference vaccine. Sixteen Brucella-free rams, 6 months of age, were vaccinated subcutaneously with 4.18 x 10(10) c.f.u. RB51. Sixteen rams of the same condition and age were vaccinated subcutaneously the same day with 1.1 x 10(9) c.f.u. Rev 1. Fifteen similar rams were kept unvaccinated as controls. Six months after vaccination all rams were challenged with 3 x 10(9) c.f.u. B. ovis and slaughtered 8 weeks thereafter for bacteriological and pathological studies. The percentage of rams that were found infected was 68% (Rev 1), 100% (RB51) and 100% (controls). At necropsy, the percentage of organs found to be infected was significantly lower (p < 0.0005) in Rev 1-vaccinated (34%) than in RB51-vaccinated rams (74%) or controls (69%). In conclusion, the RB51 vaccine did not confer protective immunity against B. ovis in rams.
- Published
- 1995
- Full Text
- View/download PDF
24. Vaccination with Brucella abortus rough mutant RB51 protects BALB/c mice against virulent strains of Brucella abortus, Brucella melitensis, and Brucella ovis.
- Author
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Jiménez de Bagüés MP, Elzer PH, Jones SM, Blasco JM, Enright FM, Schurig GG, and Winter AJ
- Subjects
- Animals, Bacterial Vaccines immunology, Dose-Response Relationship, Immunologic, Female, Hypersensitivity, Delayed immunology, Immunization, Passive, Mice, Mice, Inbred BALB C, Vaccination, Brucella immunology, Brucella abortus immunology, Brucella melitensis immunology, Brucellosis prevention & control
- Abstract
Vaccination of BALB/c mice with live Brucella abortus RB51, a stable rough mutant, produced protection against challenge with virulent strains of Brucella abortus, Brucella melitensis, and Brucella ovis. Passive-transfer experiments indicated that vaccinated mice were protected against B. abortus 2308 through cell-mediated immunity, against B. ovis PA through humoral immunity, and against B. melitensis 16M through both forms of immunity. Live bacteria were required for the induction of protective cell-mediated immunity; vaccination with whole killed cells of strain RB51 failed to protect mice against B. abortus 2308 despite development of good delayed-type hypersensitivity reactions. Protective antibodies against the heterologous species were generated in vaccinated mice primarily through anamnestic responses following challenge infections. Growth of the antigenically unrelated bacterium Listeria monocytogenes in the spleens of vaccinated mice indicated that nonspecific killing by residual activated macrophages contributed minimally to protection. These results encourage the continued investigation of strain RB51 as an alternative vaccine against heterologous Brucella species. However, its usefulness against B. ovis would be limited if, as suggested here, epitopes critical for protective cell-mediated immunity are not shared between B. abortus and B. ovis.
- Published
- 1994
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25. Protective immunity to Brucella ovis in BALB/c mice following recovery from primary infection or immunization with subcellular vaccines.
- Author
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Jiménez de Bagüés MP, Elzer PH, Blasco JM, Marín CM, Gamazo C, and Winter AJ
- Subjects
- Animals, Antibodies, Bacterial blood, Antigens, Bacterial isolation & purification, Bacterial Vaccines isolation & purification, Brucella growth & development, Brucellosis immunology, Brucellosis microbiology, Female, Immunity, Cellular, Immunization, Passive, Mice, Mice, Inbred BALB C, Sheep, T-Lymphocyte Subsets immunology, Vaccination, Bacterial Vaccines pharmacology, Brucella immunology, Brucellosis prevention & control
- Abstract
Experiments were performed with BALB/c mice to elucidate the roles of humoral and cell-mediated immune responses in the acquisition of protective immunity to Brucella ovis and to compare infection immunity with immunity developed through vaccination with a hot saline extract (HS) of B. ovis. Mice convalescing from a primary infection with B. ovis displayed a high level of resistance to reinfection, as evidenced by splenic bacterial counts decreased over 10,000-fold from control groups at 2 weeks after challenge. Passive transfer assays revealed that protection was mediated by both T lymphocytes and antibodies but that antibodies had a substantially greater role on the basis of log units of protection that were transferred. Antibodies specific for HS proteins in sera from convalescent mice were predominantly of the immunoglobulin G 2a and 3 isotypes. Vaccination with HS conferred good protection against B. ovis, but protection was greatly enhanced by the incorporation of QS-21 or other adjuvants. Protection provided by the HS vaccine resulted largely from immune responses to its protein moieties. A critical evaluation of the protective efficacy of the rough lipopolysaccharide component of HS was precluded by its poor immunogenicity in BALB/c mice. HS-QS-21 afforded protection against challenge infection with B. ovis as good as that which developed after a primary infection and as good as or better than that provided by attenuated Brucella melitensis vaccine strain Rev 1. Passive transfer experiments confirmed that the magnitudes of both humoral and cell-mediated forms of protective immunity were equivalent in mice vaccinated with HS-QS-21 and those recovering from a primary infection. Protective immunity to B. ovis in mice therefore resembled that to Brucella abortus, except that the relative roles of humoral and cell-mediated immunity, rather than being equivalent, were shifted toward a greater role for antibodies.
- Published
- 1994
- Full Text
- View/download PDF
26. Efficacy of Brucella suis strain 2 vaccine against Brucella ovis in rams.
- Author
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Blasco JM, Marín C, Jiménez de Bagüés MP, and Barberán M
- Subjects
- Animals, Antibody Formation immunology, Brucellosis immunology, Male, Sheep, Sheep Diseases immunology, Vaccination, Brucella immunology, Brucella Vaccine pharmacology, Brucellosis prevention & control, Brucellosis veterinary, Sheep Diseases microbiology, Sheep Diseases prevention & control
- Abstract
The protective efficacy against Brucella ovis of live vaccine Brucella suis strain 2 (S2) and Brucella melitensis strain Rev 1 has been evaluated in rams. Fourteen 4-month-old Brucella-free Aragonesa rams were vaccinated conjunctivally with 2 x 10(9) c.f.u. S2. Sixteen rams of the same breed, condition and age were conjunctivally vaccinated the same day with 1.6 x 10(9) Rev 1. Thirteen rams were unvaccinated controls. Eight months after vaccination all rams were challenged with 6 x 10(9) c.f.u. B. ovis and slaughtered 2 months thereafter for bacteriological and pathological studies. The percentage of infection in the group vaccinated with Rev 1 (43.7%) was significantly lower (p < 0.05) than that of the S2-vaccinated animals (78.6%) and unvaccinated controls (84.6%). No significant differences were found when comparing the percentages of infection corresponding to S2-vaccinated and control groups. The degree of infection (percentage of necropsy samples infected) was significantly lower in Rev 1-vaccinated (13%) than in S2-vaccinated (36.9%) or control groups (47.4%) (p < 0.001). However, no significant differences were found when comparing S2-vaccinated and control groups.
- Published
- 1993
- Full Text
- View/download PDF
27. Evaluation of whole cell and subcellular vaccines against Brucella ovis in rams.
- Author
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Blasco JM, Gamazo C, Winter AJ, Jiménez de Bagüés MP, Marín C, Barberán M, Moriyón I, Alonso-Urmeneta B, and Díaz R
- Subjects
- Animals, Antigens, Bacterial immunology, Brucella melitensis immunology, Brucellosis immunology, Brucellosis prevention & control, Evaluation Studies as Topic, Male, Sheep, Sheep Diseases prevention & control, Vaccines, Attenuated immunology, Vaccines, Inactivated immunology, Antibodies, Bacterial biosynthesis, Brucella immunology, Brucella Vaccine immunology, Brucellosis veterinary, Sheep Diseases immunology, Subcellular Fractions immunology
- Abstract
Five antigen preparations from Brucella ovis strain REO 198 were incorporated with the pluronic polymer L-121 and muramyl dipeptide and tested as vaccines against B. ovis infection of rams. The antigenic preparations were: (1) a fraction enriched in outer membrane proteins and rough lipopolysaccharide (hot saline extract, HS); (2) the proteins from HS substantially free of lipopolysaccharide; (3) outer membrane blebs; (4) outer membrane-peptidoglycan complexes extracted with detergent; (5) killed whole cells. The experimental vaccines were compared with two standard vaccines, rough Brucella abortus 45/20 whole killed cells in an oil based adjuvant, and live Brucella melitensis Rev 1. Immunizations with non-living vaccines were performed on two occasions, 18 weeks apart. The rams were challenged with a virulent strain of B. ovis 31 weeks after the second vaccination and slaughtered 15 weeks thereafter. Rates of infection in groups vaccinated with Rev 1 (33%), and HS (40%) were significantly lower (P < 0.005 and P < 0.025, respectively) than that in the non-vaccinated control group (87%). Strain 45/20 was the only other vaccine that conferred a significant level of protection (50%) (P < 0.05). The organ distribution of the infection and the level of colonization of infected organs did not differ significantly between infected animals in the various vaccine groups and those in the unvaccinated control group. No statistically significant relationship was detected between the magnitude of the antibody responses to the HS extract, to outer membrane proteins, or to the rough lipopolysaccharide, and freedom from infection. The results indicate that the HS extract of B. ovis may represent a useful alternative to B. melitensis Rev 1 or B. abortus 45/20 as a vaccine against B. ovis.
- Published
- 1993
- Full Text
- View/download PDF
28. Evaluation of vaccines and of antigen therapy in a mouse model for Brucella ovis.
- Author
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Jiménez de Bagüés MP, Marín CM, Barberán M, and Blasco JM
- Subjects
- Animals, Brucella immunology, Brucellosis immunology, Disease Models, Animal, Dose-Response Relationship, Immunologic, Evaluation Studies as Topic, Female, Male, Mice, Antigens, Bacterial administration & dosage, Brucella Vaccine administration & dosage, Brucellosis prevention & control, Brucellosis therapy
- Abstract
A mouse model was developed to study Brucella ovis infection. The evolution of the number of B. ovis per spleen of mice inoculated intravenously, intraperitoneally or subcutaneously was found to be independent of the sex of the mice. The number of B. ovis increased in the spleen when increasing the challenge dose up to 1.7 x 10(7). At higher doses of challenge, the response remained constant. In this model it was observed that the inoculation of Brucella melitensis Rev 1 vaccine or subcellular B. ovis hot saline antigens during both the acute and chronic phases did not modify the time course of B. ovis infection. Finally, the model was found suitable to determine the efficacy of anti-B. ovis vaccines. B. melitensis Rev 1 (2.2 x 10(5) c.f.u.) and B. suis strain 2 (1.2 x 10(7) c.f.u.) live vaccines but not the inactivated B. melitensis H38 vaccine conferred protection against B. ovis.
- Published
- 1993
- Full Text
- View/download PDF
29. An ELISA with Brucella lipopolysaccharide antigen for the diagnosis of B. melitensis infection in sheep and for the evaluation of serological responses following subcutaneous or conjunctival B. melitensis strain Rev 1 vaccination.
- Author
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Jiménez de Bagüés MP, Marín CM, Blasco JM, Moriyón I, and Gamazo C
- Subjects
- Agglutination Tests, Animals, Brucella Vaccine administration & dosage, Brucellosis diagnosis, Complement Fixation Tests, Enzyme-Linked Immunosorbent Assay, Female, Immunodiffusion, Injections, Subcutaneous veterinary, Lipopolysaccharides immunology, Male, Rose Bengal, Sheep, Vaccination veterinary, Antibodies, Bacterial blood, Brucella immunology, Brucella Vaccine immunology, Brucellosis veterinary, Sheep Diseases diagnosis
- Abstract
An indirect enzyme-linked immunosorbent assay (ELISA) with unpurified Brucella melitensis smooth lipopolysaccharide (S-LPS) as antigen was evaluated for the serological diagnosis of B. melitensis infection in sheep in comparison with the Rose Bengal (RB), complement fixation (CF), radial immunodiffusion (RID), microplate agglutination (MA) and rivanol agglutination (RIV) tests. Tests RB and CF detected as positive each of the 77 sera from B. melitensis-infected animals tested, the RID (74), MA (76) and the RIV (72) were less sensitive. However, all tests compared were negative when 77 sera from Brucella-free rams were tested. While subcutaneous Rev 1 vaccination induced high response levels in any of the tests, low level responses were obtained upon conjunctival vaccination, particularly in ELISA and RID tests.
- Published
- 1992
- Full Text
- View/download PDF
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