Brucella species lacking the major outer membrane protein Omp25 are attenuated in mice and protect against Brucella melitensis and Brucella ovis

Edmonds, Matthew D.; Cloeckaert, Axel; Elzer, Philip H.

doi:10.1016/s0378-1135(02)00110-4

Cited by 98 publications

(83 citation statements)

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“…Since Omp25 production is suspected to play an important role in Brucella virulence (12)(13)(14)18), we further investigated whether the production of group 3 Omps could be altered under various culture conditions. Indeed, it was shown that the production of VirB proteins composing the type IV secretion system were initiated (B. suis and B. canis) or increased (B. melitensis, B. ovis, or B. abortus) when grown in acidic nutrient-deprived medium (24).…”

Section: Resultsmentioning

confidence: 99%

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Characterization of New Members of the Group 3 Outer Membrane Protein Family of Brucella spp

et al. 2003

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Impairment of the omp25 gene in Brucella spp. leads to attenuated strains and confers protection to the host. Omp25 and Omp31, whose functions remain unknown, were the first characterized members of group 3 outer membrane proteins (Omps) (25 to 34 kDa). Recently, genomic and proteomic approaches identified five new putative members of this family, some of which are produced in B. melitensis or B. abortus. In the present study, using protein microsequencing, we identified new members of group 3 Omps proteins produced in B. suis. Since several monoclonal antibodies (MAbs) against Omp25 cross-reacted with other members of group 3 Omps, we also performed Western immunoblotting to compare wild-type B. suis with mutants systematically having B. suis omp25-related genes knocked out. We demonstrate the production of three paralogs of Omp31 and/or Omp25 in B. suis, and the existence of a common site of signal peptide cleavage (AXAAD), which is very similar to that present in the five homologous Omps of Bartonella quintana. The seven group 3 Omps were classified in four-subgroups on the basis of percentage amino acid sequence identities: Omp25 alone, the Omp25b-Omp25c-Omp25d cluster, the Omp31/31b subgroup, and the less related Omp22 protein (also called Omp3b). Together with previous data, our results demonstrate that all new members of group 3 Omps are produced in B. suis or in other Brucella species and we propose a nomenclature that integrates all of these proteins to facilitate the understanding of future Brucella interspecies study results.Brucellae are small, nonmotile, gram-negative coccobacilli that are able to infect a broad range of wildlife and domestic mammals. They remain a major zoonotic disease source affecting humans worldwide and are also a focus of concern as potential biological warfare agents (20). Although BrucelIa spp. are not particularly host specific, three major (B. abortus, B. melitensis, and B. suis) and minor (B. canis, B. ovis, and B. neotomae) species each have distinct host preferences and pathogenicities for humans (29). Malta fever (also known as Mediterranean, Gibraltar, or undulant fever) and porcine brucellosis-caused by B. melitensis and B. suis infection of humans, respectively-are usually by far more clinically apparent than Bang's disease (B. abortus infection), whereas among the remaining species only B. canis causes anecdotal mild infections in humans (10).The Brucella outer membrane was investigated to seek immunogenic and protective antigens for potential diagnostic and vaccine applications. The major outer membrane proteins (Omps) of Brucella spp. were thoroughly studied in this regard.

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Section: Resultsmentioning

confidence: 99%

“…The other well known Omp25 protein has been shown to be involved in the virulence of B. melitensis, B. abortus, and B. ovis (12)(13)(14). Mutants lacking Omp25 are indeed attenuated in animal models of infection, and also provide levels of protection similar to or better than the currently used attenuated vaccine strain B. melitensis Rev.1.…”

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Characterization of New Members of the Group 3 Outer Membrane Protein Family of Brucella spp

et al. 2003

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“…Smooth LPS O chain is involved in inhibition of early fusion between Brucella containing phagosomes and lysosomes in murine macrophages and mutations that inactivate the LPS biosynthetic gene, wbdA (BMEI0997), in B. suis attenuate its ability to multiply within macrophages (25). Likewise, Omp25 is implicated in virulence of B. melitensis and B. abortus, and inactivation of Omp25 in Brucella results in attenuation in BALB/c mice (11). Omp25 is an Omp3 homologue found in many pathogens or symbionts of ␣-proteobacteria, where it plays a role in bacterial surface control and host cell interactions (18).…”

Section: Discussionmentioning

confidence: 99%

Comparative Whole-Genome Hybridization Reveals Genomic Islands inBrucellaSpecies

et al. 2004

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Brucella species are responsible for brucellosis, a worldwide zoonotic disease causing abortion in domestic animals and Malta fever in humans. Based on host preference, the genus is divided into six species. Brucella abortus, B. melitensis, and B. suis are pathogenic to humans, whereas B. ovis and B. neotomae are nonpathogenic to humans and B. canis human infections are rare. Limited genome diversity exists among Brucella species. Comparison of Brucella species whole genomes is, therefore, likely to identify factors responsible for differences in host preference and virulence restriction. To facilitate such studies, we used the complete genome sequence of B. melitensis 16M, the species highly pathogenic to humans, to construct a genomic microarray. Hybridization of labeled genomic DNA from Brucella species to this microarray revealed a total of 217 open reading frames (ORFs) altered in five Brucella species analyzed. These ORFs are often found in clusters (islands) in the 16M genome. Examination of the genomic context of these islands suggests that many are horizontally acquired. Deletions of genetic content identified in Brucella species are conserved in multiple strains of the same species, and genomic islands missing in a given species are often restricted to that particular species. These findings suggest that, whereas the loss or gain of genetic material may be related to the host range and virulence restriction of certain Brucella species for humans, independent mechanisms involving gene inactivation or altered expression of virulence determinants may also contribute to these differences.Brucellosis is a zoonotic disease endemic in many areas of the world and is characterized by chronic infections, abortion, and sterility (7). In humans, brucellosis is a systemic, febrile illness resulting in osteoarthritis, endocarditis, and several neurological disorders (7,53). Brucellosis is caused by many species belonging to the genus Brucella that are aerobic facultative intracellular bacteria. Brucella species are closely related to intracellular symbionts and pathogens of plants and animals and are classified as ␣ 2 -proteobacteria based on rRNA sequence comparison (36).The genus Brucella consists of six species, designated on the basis of host preference, antigenic and biochemical characteristics as Brucella melitensis (goats and sheep), B. abortus (cattle), B. suis (pigs), B. canis (dogs), B. ovis (sheep), and B. neotomae (wood rats) (6). B. abortus, B. melitensis, and B. suis can all infect humans with similar serious disease consequences (7). B. melitensis, originally isolated as a pathogen of goats and sheep, is highly pathogenic and a frequent cause of human brucellosis. In contrast, human infections of B. ovis and B. neotomae have not been reported, and B. canis rarely causes infection in humans. Human brucellosis occurs via contact with infected animals or animal products and is common in countries where the disease is endemic in domestic animals (13). Brucella also can be readily dispersed through aerosol...

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“…Combinations of these strategies have been useful in countries with efficient veterinarian services and relatively small and well controlled herds but they may be difficult to apply to large herds or when extensive breeding and transhumance systems exist. Vaccines devoid of diagnostically significant antigens combined with diagnostic tests that use such antigens represent an alternative [1,20,38,113]. The relevant diagnostic antigen in B. abortus and B. melitensis infections is the smooth (S) lipopolysaccharide (LPS) present in field strains as well as in S19 and Rev 1.…”

Section: Rough Brucellosis Vaccinesmentioning

confidence: 99%

Rough vaccines in animal brucellosis: Structural and genetic basis and present status

Grilló²,

et al. 2004

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-Brucellosis control and eradication requires serological tests and vaccines. Effective classical vaccines (S19 in cattle and Rev 1 in small ruminants), however, induce antibodies to the O-polysaccharide of the lipopolysaccharide which may be difficult to distinguish from those resulting from infection and may thus complicate diagnosis. Rough attenuated mutants lack the O-polysaccharide and would solve this problem if eliciting protective immunity; the empirically obtained rough mutants 45/20 and RB51 have been used as vaccines. Strain 45/20 is reportedly unstable and it is not presently used. RB51 is increasingly used instead of S19 in some countries but it is rifampicin resistant and its effectiveness is controversial. Some controlled experiments have found good or absolute protection in adult cattle vaccinated orally (full dose) or subcutaneously (reduced dose) and in one field experiment, RB51 was reported to afford absolute protection to calves and to perform better than S19. Controlled experiments in calves, however, have shown reduced doses of RB51 to be ineffective, full doses only partially effective, and RB51 less effective than S19 against severe challenges. Moreover, other observations suggest that RB51 is ineffective when prevalence is high. RB51 is not useful in sheep and evidence in goats is preliminary and contradictory. Rough mutants obtained by molecular biology methods on the knowledge of the genetics and structure of Brucella lipopolysaccharide may offer alternatives. The B. abortus manB core (rfbK) mutant seems promising in cattle, and analyses in mice suggest that mutations affecting only the O-polysaccharide result in better vaccines than those affecting both core and O-polysaccharide. Possible uses of rough vaccines also include boosting immunity by revaccination but solid evidence on its effectiveness, safety and practicality is not available.

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Brucella species lacking the major outer membrane protein Omp25 are attenuated in mice and protect against Brucella melitensis and Brucella ovis

Cited by 98 publications

References 25 publications

Characterization of New Members of the Group 3 Outer Membrane Protein Family of Brucella spp

Characterization of New Members of the Group 3 Outer Membrane Protein Family of Brucella spp

Comparative Whole-Genome Hybridization Reveals Genomic Islands inBrucellaSpecies

Rough vaccines in animal brucellosis: Structural and genetic basis and present status

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