The attenuated virulence of a <scp>B</scp>urkholderia cenocepacia <scp>paaABCDE</scp> mutant is due to inhibition of quorum sensing by release of phenylacetic acid

Pribytkova, Tanya; Lightly, Tasia Joy; Kumar, Brijesh; Bernier, Steve P.; Sorensen, John L.; Surette, Michael G.; Cardona, Silvia T.

doi:10.1111/mmi.12771

Cited by 18 publications

(29 citation statements)

References 67 publications

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“…Creation and phenotypic characterization of a paaK double mutant. Previously, we demonstrated a link between the attenuation of B. cenocepacia K56-2 ΔpaaABCDE and the release of PAA (18). However, the interruption of the pathway at this step could also result in an accumulation of PAA-CoA because PAA is converted to PAA-CoA by a PaaK ligase (Fig.…”

Section: Resultsmentioning

confidence: 88%

“…We previously found that CepIR-regulated virulence traits and cepI and cepR promoter activity were downregulated in a B. cenocepacia mutant of the paaABCDE operon that released PAA (18). We also demonstrated that PAA could be produced to detectable levels in wild-type B. cenocepacia K56-2 under certain conditions, suggesting a potential physiological role of the regulation of virulence by this molecule (21).…”

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confidence: 74%

“…Several lines of evidence point to metabolic adaptation as an important component of virulence regulation (12)(13)(14)(15). In this context, high levels of phenylacetic acid (PAA) have been linked to evasion of the immune response by Acinetobacter (16), inhibition of pathogenicity of the fungus Rhizoctonia solani (17), and downregulation of virulence gene expression in B. cenocepacia (18). The PAA degradation pathway is a central route by which diverse aromatic compounds, such as phenylalanine, converge and are directed to the tricarboxylic acid (TCA) cycle (19).…”

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confidence: 99%

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Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

Lightly

Frejuk

Groleau

et al. 2019

Appl Environ Microbiol

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During phenylalanine catabolism, phenylacetic acid (PAA) is converted to phenylacetyl coenzyme A (PAA-CoA) by a ligase, PaaK, and then PAA-CoA is epoxidized by a multicomponent monooxygenase, PaaABCDE, before further degradation through the tricarboxylic acid (TCA) cycle. In the opportunistic pathogen Burkholderia cenocepacia, loss of paaABCDE attenuates virulence factor expression, which is under the control of the LuxIR-like quorum sensing (QS) system, CepIR. To further investigate the link between CepIR-regulated virulence and PAA catabolism, we created knockout mutants of the first step of the pathway (PAA-CoA synthesis by PaaK) and characterized them in comparison to a paaABCDE mutant using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and virulence assays. We found that while loss of PaaABCDE decreased virulence, deletion of the paaK genes resulted in a more virulent phenotype than that of the wild-type strain. Deletion of either paaK or paaABCDE led to higher levels of released PAA but no differences in levels of internal accumulation compared to the wild-type level. While we found no evidence of direct cepIR downregulation by PAA-CoA or PAA, a low-virulence cepR mutant reverted to a virulent phenotype upon removal of the paaK genes. On the other hand, removal of paaABCDE in the cepR mutant did not impact its attenuated phenotype. Together, our results suggest an indirect role for PAA-CoA in suppressing B. cenocepacia CepIR-activated virulence. IMPORTANCE The opportunistic pathogen Burkholderia cenocepacia uses a chemical signal process called quorum sensing (QS) to produce virulence factors. In B. cenocepacia, QS relies on the presence of the transcriptional regulator CepR which, upon binding QS signal molecules, activates virulence. In this work, we found that even in the absence of CepR, B. cenocepacia can elicit a pathogenic response if phenylacetyl-CoA, an intermediate of the phenylacetic acid degradation pathway, is not produced. Instead, accumulation of phenylacetyl-CoA appears to attenuate pathogenicity. Therefore, we have discovered that it is possible to trigger virulence in the absence of CepR, challenging the classical view of activation of virulence by this QS mechanism. Our work provides new insight into the relationship between metabolism and virulence in opportunistic bacteria. We propose that in the event that QS signaling molecules cannot accumulate to trigger a pathogenic response, a metabolic signal can still activate virulence in B. cenocepacia.

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Section: Resultsmentioning

confidence: 88%

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confidence: 74%

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confidence: 99%

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Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

Lightly

Frejuk

Groleau

et al. 2019

Appl Environ Microbiol

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“…In Burkholderia cenocepacia, a Gram-negative pathogen related to A. baumannii, deletion of genes in the phenylalanine degradation pathway (paaABCDE) led to accumulation of phenylacetic acid and inhibited bacterial quorum sensing (36). Virulence attenuation has also been shown with disruption of the paa catabolic pathway; however, the mechanism of this remains unclear (37).…”

Section: Discussionmentioning

confidence: 99%

Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis

Bhuiyan

Ellett

Murray

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

101

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Innate cellular immune responses are a critical first-line defense against invading bacterial pathogens. Leukocyte migration from the bloodstream to a site of infection is mediated by chemotactic factors that are often host-derived. More recently, there has been a greater appreciation of the importance of bacterial factors driving neutrophil movement during infection. Here, we describe the development of a zebrafish infection model to study Acinetobacter baumannii pathogenesis. By using isogenic A. baumannii mutants lacking expression of virulence effector proteins, we demonstrated that bacterial drivers of disease severity are conserved between zebrafish and mammals. By using transgenic zebrafish with fluorescent phagocytes, we showed that a mutation of an established A. baumannii global virulence regulator led to marked changes in neutrophil behavior involving rapid neutrophil influx to a localized site of infection, followed by prolonged neutrophil dwelling. This neutrophilic response augmented bacterial clearance and was secondary to an impaired A. baumannii phenylacetic acid catabolism pathway, which led to accumulation of phenylacetate. Purified phenylacetate was confirmed to be a neutrophil chemoattractant. These data identify a previously unknown mechanism of bacterial-guided neutrophil chemotaxis in vivo, providing insight into the role of bacterial metabolism in host innate immune evasion. Furthermore, the work provides a potentially new therapeutic paradigm of targeting a bacterial metabolic pathway to augment host innate immune responses and attenuate disease.

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“…Phenylacetic acid (PAA) is a signal molecule that could be involved in microbial interactions with the host 57 . The phenylacetic acid (PAA) catabolic pathway was shown to be required for the full pathogenicity of B. cenocepacia in a Caenorhabditis elegans nematode infection model 58 . Nevertheless, B. seminalis TC3.4.2R3 does not possess all genes of the PAA pathway.…”

Section: Discussionmentioning

confidence: 99%

Environmental interactions are regulated by temperature in Burkholderia seminalis TC3.4.2R3

Gonçalves

Denman

Ferreira

et al. 2019

Sci Rep

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Burkholderia seminalis strain TC3.4.2R3 is an endophytic bacterium isolated from sugarcane roots that produces antimicrobial compounds, facilitating its ability to act as a biocontrol agent against phytopathogenic bacteria. In this study, we investigated the thermoregulation of B. seminalis TC3.4.2R3 at 28 °C (environmental stimulus) and 37 °C (host-associated stimulus) at the transcriptional and phenotypic levels. The production of biofilms and exopolysaccharides such as capsular polysaccharides and the biocontrol of phytopathogenic fungi were enhanced at 28 °C. At 37 °C, several metabolic pathways were activated, particularly those implicated in energy production, stress responses and the biosynthesis of transporters. Motility, growth and virulence in the Galleria mellonella larvae infection model were more significant at 37 °C. Our data suggest that the regulation of capsule expression could be important in virulence against G. mellonella larvae at 37 °C. In contrast, B. seminalis TC3.4.2R3 failed to cause death in infected BALB/c mice, even at an infective dose of 10 7 CFU.mL −1 . We conclude that temperature drives the regulation of gene expression in B. seminalis during its interactions with the environment.

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The attenuated virulence of a Burkholderia cenocepacia paaABCDE mutant is due to inhibition of quorum sensing by release of phenylacetic acid

Cited by 18 publications

References 67 publications

Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis

Environmental interactions are regulated by temperature in Burkholderia seminalis TC3.4.2R3

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