A Brucella Virulence Factor Targets Macrophages to Trigger B-cell Proliferation

Spera, Juan Manuel; Herrmann, Claudia; Roset, Mara S.; Comerci, Diego J.; Ugalde, Juan Esteban

doi:10.1074/jbc.m113.453282

Cited by 16 publications

(16 citation statements)

References 32 publications

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“…We have recently shed some light into the molecular mechanism of PrpA. Although this virulence factor is a B-cell mitogen, we have shown that it actually targets CD11b + F4/80 + macrophages, where it is translocated during infection [7]. PrpA treated macrophages release soluble factor/s ultimately responsible for B-lymphocyte proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of Brucella to establish chronic infections in the face of an ongoing immune response, suggests the existence of bacterial virulence factors with immunomodulatory effects. We have previously described a Brucella abortus virulence factor ( prpA, for Proline Racemase Protein A) that i) is secreted during infection, ii) interacts with NMMII-A in macrophages and iii) induces the release of soluble factors responsible for B-cell proliferation in vitro [7, 8]. We also showed that prpA is required for the establishment of the chronic phase of infection in mice [8].…”

Section: Introductionmentioning

confidence: 99%

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Brucella alters the immune response in a prpA-dependent manner

Spera

Comerci

Ugalde

2014

Microbial Pathogenesis

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Brucellosis, a disease caused by the gram-negative bacterium Brucella sp, is a widespread zoonosis that inflicts important animal and human health problems, especially in developing countries. One of the hallmarks of Brucella infection is its capacity to establish a chronic infection, characteristic that depends on a wide repertoire of virulence factors among which are immunomodulatory proteins such as PrpA (encoding the proline racemase protein A or hydroxyproline-2-epimerase), involved in the establishment of the chronic phase of the infectious process that we have previously identified and characterized. We report here that, in vivo, B. abortus prpA is responsible for an increment in the B-cell number and in the specific antibody response and that these antibodies promote cell infection. We additionally found that Brucella alters the cytokine levels of IFN-γ, IL-10, TGFβ1 and TNFα during the acute phase of the infectious process in a prpA dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Brucella alters the immune response in a prpA-dependent manner

Spera

Comerci

Ugalde

2014

Microbial Pathogenesis

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“…B. abortus has the ability to enter and replicate inside mammalian cells (Gorvel & Moreno, 2002), which enables immune evasion and can reduce efficacy of antimicrobial therapies. There are several molecular features of the B. abortus cell that play a role in its ability to infect and replicate in mammalian hosts (Atluri et al, 2011, Batut et al, 2004, Byndloss & Tsolis, 2016, Celli, 2006, de Figueiredo et al, 2015, Gorvel, 2008, including smooth lipopolysaccharide (Lapaque et al, 2005, Cardoso et al, 2006, Conde-Alvarez et al, 2012, Smith, 2018, the type IV secretion system (Byndloss & Tsolis, 2016, O'Callaghan et al, 1999, Delrue et al, 2001, den Hartigh et al, 2008, and secreted protein effectors (de Barsy et al, 2011, Myeni et al, 2013, Spera et al, 2013. Here, we report a functional and structural analysis of envelope integrity protein A (EipA), a protein required for B. abortus envelope stress resistance and infection.…”

Section: Introductionmentioning

confidence: 91%

“…B. abortus has the ability to enter and replicate inside mammalian cells (1), which enables immune evasion and can reduce efficacy of antimicrobial therapies. There are several molecular features of B. abortus that play a key role in its ability to infect hosts (1)(2)(3)(4)(5)(6)(7)(8), including smooth lipopolysaccharide (SLPS) (9)(10)(11)(12), the type IV secretion system (6,(13)(14)(15), and secreted protein effectors (16)(17)(18)(19). Here, we report a functional and structural analysis of envelope integrity protein A (EipA), a protein required for B. abortus envelope stress resistance and infection.…”

Section: Introductionmentioning

confidence: 99%

Periplasmic protein EipA determines envelope stress resistance and virulence inBrucella abortus

Herrou¹,

Willett²,

Fiebig³

et al. 2018

Preprint

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Molecular components of the Brucella abortus cell envelope, including lipopolysaccharide, play a major role in its ability to infect, colonize and survive inside mammalian host cells. We have defined a role for a conserved gene of unknown function in B. abortus envelope stress resistance and infection. Expression of this gene, which we name eipA, is directly activated by the essential cell cycle regulator, CtrA. eipA encodes a soluble periplasmic protein that adopts an unusual eight-stranded β -barrel fold. Deletion of eipA attenuates replication and survival in macrophage and mouse infection models, and results in sensitivity to cell envelope stressors in vitro. Transposon disruption of genes required for LPS O-polysaccharide biosynthesis is synthetically lethal with eipA deletion. This genetic connection between O-polysaccharide and eipA is corroborated by our discovery that eipA is essential in Brucella ovis, a rough species that harbors mutations in several genes required for O-polysaccharide production. Conditional depletion of eipA expression in B. ovis results in a cell chaining phenotype, providing evidence that eipA directly or indirectly influences cell division in Brucella. Our data provide evidence that EipA is a molecular determinant of Brucella virulence that functions to maintain cell envelope integrity and influences cell division.

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“…B. abortus has the ability to enter and replicate inside mammalian cells (Gorvel and Moreno, 2002), which enables immune evasion and can reduce efficacy of antimicrobial therapies. There are several molecular features of the B. abortus cell that play a role in its ability to infect and replicate in mammalian hosts (Batut et al, 2004;Celli, 2006;Gorvel, 2008;Atluri et al, 2011;de Figueiredo et al, 2015;Byndloss and Tsolis, 2016), including smooth lipopolysaccharide (Lapaque et al, 2005;Cardoso et al, 2006;Conde-Alvarez et al, 2012;Smith, 2018), the type IV secretion system (O'Callaghan et al, 1999;Delrue et al, 2001;den Hartigh et al, 2008;Byndloss and Tsolis, 2016) and secreted protein effectors (de Barsy et al, 2011;Myeni et al, 2013;Spera et al, 2013). Here, we report a functional and structural analysis of envelope integrity protein A (EipA), a protein required for B. abortus envelope stress resistance and infection.…”

Section: Introductionmentioning

confidence: 99%

Periplasmic protein EipA determines envelope stress resistance and virulence in Brucella abortus

Herrou

Willett

Fiebig

et al. 2019

Molecular Microbiology

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Summary Molecular components of the Brucella abortus cell envelope play a major role in its ability to infect, colonize and survive inside mammalian host cells. In this study, we have defined a role for a conserved gene of unknown function in B. abortus envelope stress resistance and infection. Expression of this gene, which we name eipA, is directly activated by the essential cell cycle regulator, CtrA. eipA encodes a soluble periplasmic protein that adopts an unusual eight‐stranded β‐barrel fold. Deletion of eipA attenuates replication and survival in macrophage and mouse infection models, and results in sensitivity to treatments that compromise the cell envelope integrity. Transposon disruption of genes required for LPS O‐polysaccharide biosynthesis is synthetically lethal with eipA deletion. This genetic connection between O‐polysaccharide and eipA is corroborated by our discovery that eipA is essential in Brucella ovis, a naturally rough species that harbors mutations in several genes required for O‐polysaccharide production. Conditional depletion of eipA expression in B. ovis results in a cell chaining phenotype, providing evidence that eipA directly or indirectly influences cell division in Brucella. We conclude that EipA is a molecular determinant of Brucella virulence that functions to maintain cell envelope integrity and influences cell division.

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A Brucella Virulence Factor Targets Macrophages to Trigger B-cell Proliferation

Cited by 16 publications

References 32 publications

Brucella alters the immune response in a prpA-dependent manner

Brucella alters the immune response in a prpA-dependent manner

Periplasmic protein EipA determines envelope stress resistance and virulence inBrucella abortus

Periplasmic protein EipA determines envelope stress resistance and virulence in Brucella abortus

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