Is Brucella an enteric pathogen?

Gorvel, Jean‐Pierre; Moreno, Edgardo; Moriyón, Ignacio

doi:10.1038/nrmicro2012-c1

Cited by 21 publications

(22 citation statements)

References 11 publications

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“…9 Despite the experimental evidence that Brucella is able to penetrate the intestinal barrier following oral inoculation 40, 41 , the specific mechanism remains to be determined. In fact, intragastric infection of mice was found to be relatively inefficient and required a high infectious dose.…”

Section: Discussionmentioning

confidence: 99%

“…1, 8 Inhalation or mucosal exposure to aerosolized bacteria from contact with the infected animal’s vaginal secretions, urine, feces, or blood (especially amongst livestock producers, abattoir workers, and veterinarians) can also cause disease transmission. 8 What is shared between animal and human Brucella transmission is the naso-oropharyngeal mucosa being impacted by Brucella , and not so much the intestinal mucosa 9 , despite oral ingestion of contaminated foods. Given the relevance of mucosal exposure for infection by Brucella , a vaccine aimed at immunizing head and neck mucosal tissues has a high potential of success.…”

Section: Introductionmentioning

confidence: 99%

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Nasal vaccination stimulates CD8⁺ T cells for potent protection against mucosal Brucella melitensis challenge

et al. 2016

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Brucellosis remains a significant zoonotic threat worldwide. Humans and animals acquire infection via their oropharynx and upper respiratory tract following oral or aerosol exposure. After mucosal infection, brucellosis develops into a systemic disease. Mucosal vaccination could offer a viable alternative to conventional injection practices to deter disease. Using a nasal vaccination approach, the ΔznuA B. melitensis was found to confer potent protection against pulmonary Brucella challenge, and reduce colonization of spleens and lungs by more than 2500-fold, with more than 50% of vaccinated mice showing no detectable brucellae. Furthermore, tenfold more brucellae-specific, IFN-γ-producing CD8+ T cells than CD4+ T cells were induced in the spleen and respiratory lymph nodes. Evaluation of pulmonary and splenic CD8+ T cells from mice vaccinated with ΔznuA B. melitensis revealed that these expressed an activated effector memory (CD44hiCD62LloCCR7lo) T cells producing elevated levels of IFN-γ, TNF-α, perforin, and granzyme B. To assess the relative importance of these increased numbers of CD8+ T cells, CD8−/− mice were challenged with virulent B. melitensis, and they showed markedly increased bacterial loads in organs in contrast to similarly challenged CD4−/− mice. Only ΔznuA B. melitensis- and Rev-1-vaccinated CD4−/− and wild-type mice, not CD8−/− mice, were completely protected against Brucella challenge. Determination of cytokines responsible for conferring protection showed the relative importance of IFN-γ, but not IL-17. Unlike wild-type mice, IL-17 was greatly induced in IFN-γ−/− mice, but IL-17 could not substitute for IFN-γ’s protection, although an increase in brucellae dissemination was observed upon in vivo IL-17 neutralization. These results show that nasal ΔznuA B. melitensis vaccination represents an attractive means to stimulate systemic and mucosal immune protection via CD8+ T cell engagement.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nasal vaccination stimulates CD8⁺ T cells for potent protection against mucosal Brucella melitensis challenge

et al. 2016

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“…However, the gastrointestinal route is inefficacious to infect humans [7,93] and mice [91] with Brucella . In addition to the challenges posed by the local microbiota, epithelial layers and specific local immune responses, the gastric acid pH and bile salts negatively affect bacteria that, like brucellae, hardly or not at all grow at pH below 5 and have outer membranes that are not barriers to hydrophobic substances [94]. The difficulties in infecting mice by this route may also be related to the robust local resistance associated with the presence of specialized Paneth cells in the intestinal tract.…”

Section: Infection Modelsmentioning

confidence: 99%

What have we learned from brucellosis in the mouse model?

Grilló

Blasco

Gorvel

et al. 2012

Vet Res

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191

219

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Brucellosis is a zoonosis caused by Brucella species. Brucellosis research in natural hosts is often precluded by practical, economical and ethical reasons and mice are widely used. However, mice are not natural Brucella hosts and the course of murine brucellosis depends on bacterial strain virulence, dose and inoculation route as well as breed, genetic background, age, sex and physiological statu of mice. Therefore, meaningful experiments require a definition of these variables. Brucella spleen replication profiles are highly reproducible and course in four phases: i), onset or spleen colonization (first 48 h); ii), acute phase, from the third day to the time when bacteria reach maximal numbers; iii), chronic steady phase, where bacterial numbers plateaus; and iv), chronic declining phase, during which brucellae are eliminated. This pattern displays clear physiopathological signs and is sensitive to small virulence variations, making possible to assess attenuation when fully virulent bacteria are used as controls. Similarly, immunity studies using mice with known defects are possible. Mutations affecting INF-γ, TLR9, Myd88, Tγδ and TNF-β favor Brucella replication; whereas IL-1β, IL-18, TLR4, TLR5, TLR2, NOD1, NOD2, GM-CSF, IL/17r, Rip2, TRIF, NK or Nramp1 deficiencies have no noticeable effects. Splenomegaly development is also useful: it correlates with IFN-γ and IL-12 levels and with Brucella strain virulence. The genetic background is also important: Brucella-resistant mice (C57BL) yield lower splenic bacterial replication and less splenomegaly than susceptible breeds. When inoculum is increased, a saturating dose above which bacterial numbers per organ do not augment, is reached. Unlike many gram-negative bacteria, lethal doses are large (≥ 108 bacteria/mouse) and normally higher than the saturating dose. Persistence is a useful virulence/attenuation index and is used in vaccine (Residual Virulence) quality control. Vaccine candidates are also often tested in mice by determining splenic Brucella numbers after challenging with appropriate virulent brucellae doses at precise post-vaccination times. Since most live or killed Brucella vaccines provide some protection in mice, controls immunized with reference vaccines (S19 or Rev1) are critical. Finally, mice have been successfully used to evaluate brucellosis therapies. It is concluded that, when used properly, the mouse is a valuable brucellosis model.

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“…occurs through the intestine. In fact, several observations indicate that the mucosae of the face area (tonsils, lymph nodes, and conjunctival and respiratory mucosae), are the normal sites of entry of Brucella (36), which is consistent with the absence of a functional GAD system in most pathogenic Brucella species. Our previous results with B. microti showed that the loss of a functional GAD system significantly reduces the number of living bacteria recovered from the target organs liver and spleen after oral infection of mice (33).…”

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confidence: 71%

Glutamate Decarboxylase-Dependent Acid Resistance in Brucella spp.: Distribution and Contribution to Fitness under Extremely Acidic Conditions

Damiano

Bastianelli

Dahouk

et al. 2015

Appl Environ Microbiol

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f Brucella is an expanding genus of major zoonotic pathogens, including at least 10 genetically very close species occupying a wide range of niches from soil to wildlife, livestock, and humans. Recently, we have shown that in the new species Brucella microti, the glutamate decarboxylase (Gad)-dependent system (GAD system) contributes to survival at a pH of 2.5 and also to infection in mice by the oral route. In order to study the functionality of the GAD system in the genus Brucella, 47 isolates, representative of all known species and strains of this genus, and 16 strains of the closest neighbor genus, Ochrobactrum, were studied using microbiological, biochemical, and genetic approaches. In agreement with the genome sequences, the GAD system of classical species was not functional, unlike that of most strains of Brucella ceti, Brucella pinnipedialis, and newly described species (B. microti, Brucella inopinata BO1, B. inopinata-like BO2, and Brucella sp. isolated from bullfrogs). In the presence of glutamate, these species were more acid resistant in vitro than classical terrestrial brucellae. Expression in trans of the gad locus from representative Brucella species in the Escherichia coli MG1655 mutant strain lacking the GAD system restored the acid-resistant phenotype. The highly conserved GAD system of the newly described or atypical Brucella species may play an important role in their adaptation to acidic external and host environments. Furthermore, the GAD phenotype was shown to be a useful diagnostic tool to distinguish these latter Brucella strains from Ochrobactrum and from classical terrestrial pathogenic Brucella species, which are GAD negative. Brucellae are the etiologic agents of brucellosis, the most widespread bacterial zoonosis, infecting livestock and humans (human incidence, 500,000/year). The disease is endemic in the Mediterranean, in Near East and Middle East countries, and in Latin America (1, 2). These pathogens are classified as different species on the basis of specific phenotypic traits and their natural hosts (3): Brucella melitensis (isolated from goats and sheep), Brucella abortus (cattle and bison), Brucella suis (pigs and wild boar), and Brucella canis (dogs). Transmitted to humans via the mucosal, cutaneous, respiratory or, most frequently, oral route, these species may induce undulant fever (Malta fever) and a wide range of clinical manifestations, including encephalitis and endocarditis. With a few exceptions, Brucella species isolated from marine mammals (Brucella pinnipedialis and Brucella ceti) have not been described as human pathogens. Two other species are nonpathogenic for humans: Brucella ovis (sheep) and Brucella neotomae (desert woodrat) (3). Being known for 20 years or longer, these eight species are considered "classical". More recently, three "new" species/strains were identified: B. microti from common vole, red fox, and also soil (4-7) and Brucella inopinata BO1 and B. inopinata-like BO2 from patients with a breast implant infection (8, 9) and a chronic destructiv...

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Is Brucella an enteric pathogen?

Abstract: International audienc

Cited by 21 publications

References 11 publications

Nasal vaccination stimulates CD8⁺ T cells for potent protection against mucosal Brucella melitensis challenge

Nasal vaccination stimulates CD8⁺ T cells for potent protection against mucosal Brucella melitensis challenge

What have we learned from brucellosis in the mouse model?

Glutamate Decarboxylase-Dependent Acid Resistance in Brucella spp.: Distribution and Contribution to Fitness under Extremely Acidic Conditions

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Is Brucella an enteric pathogen?

Abstract: International audienc

Cited by 21 publications

References 11 publications

Nasal vaccination stimulates CD8+ T cells for potent protection against mucosal Brucella melitensis challenge

Nasal vaccination stimulates CD8+ T cells for potent protection against mucosal Brucella melitensis challenge

What have we learned from brucellosis in the mouse model?

Glutamate Decarboxylase-Dependent Acid Resistance in Brucella spp.: Distribution and Contribution to Fitness under Extremely Acidic Conditions

Contact Info

Product

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Nasal vaccination stimulates CD8⁺ T cells for potent protection against mucosal Brucella melitensis challenge

Nasal vaccination stimulates CD8⁺ T cells for potent protection against mucosal Brucella melitensis challenge