Contribution of Asparagine Catabolism to Salmonella Virulence

McLaughlin, Patrick A.; McClelland, Michael; Yang, Hee-Jeong; Porwollik, Steffen; Bogomolnaya, Lydia M.; Chen, Juei‐Suei; Andrews‐Polymenis, Helene; Velden, Adrianus W. M. van der

doi:10.1128/iai.00740-16

Cited by 13 publications

(14 citation statements)

References 40 publications

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“…However, a single mutant lacking ansB was partially defective. A complete loss of growth was observed with an ansA ansB double mutant, consistent with previous reports (9). Adding a fraE mutation to either the ansB mutant strain or the ansA ansB mutant strain had no additional effect.…”

Section: Resultssupporting

confidence: 91%

“…During our studies of the fra locus of Salmonella, we found that a fraE mutant was only partially defective for growth on F-Asn as the sole carbon source (6). Two other asparaginases (AnsA and AnsB) mediate nitrogen assimilation and contribute to virulence (9)(10)(11). Because AnsA is cytoplasmic and AnsB is periplasmic (12, 13), we postulated that AnsB was contributing to the growth of a fraE mutant on F-Asn.…”

Section: Resultsmentioning

confidence: 99%

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Salmonella FraE, an Asparaginase Homolog, Contributes to Fructose-Asparagine but Not Asparagine Utilization

et al. 2017

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Salmonella enterica can utilize fructose-asparagine (F-Asn) as a source of carbon and nitrogen. This capability has been attributed to five genes in the fra locus. Previously, we determined that mutations in fraB (deglycase), fraD (kinase), or fraA (transporter) eliminated the ability of Salmonella to grow on F-Asn, while a mutation in fraE allowed partial growth. We hypothesized that FraE, a putative periplasmic fructose-asparaginase, converts F-Asn to NH4 + and fructose-aspartate (F-Asp). FraA could then transport F-Asp into the cytoplasm for subsequent catabolism. Here, we report that growth of the fraE mutant on F-Asn is caused by a partially redundant activity provided by AnsB, a periplasmic asparaginase. Indeed, a fraE ansB double mutant is unable to grow on F-Asn. Moreover, biochemical assays using periplasmic extracts of mutants that express only FraE or AnsB confirmed that each of these enzymes converts F-Asn to F-Asp and NH4 +. However, FraE does not contribute to growth on asparagine. We tested and confirmed the hypothesis that a fraE ansB mutant can grow on F-Asp, while mutants lacking fraA, fraD, or fraB cannot. This finding provides strong evidence that FraA transports F-Asp but not F-Asn from the periplasm to the cytoplasm. Previously, we determined that F-Asn is toxic to a fraB mutant due to the accumulation of the FraB substrate, 6-phosphofructose-aspartate (6-P-F-Asp). Here, we found that, as expected, a fraB mutant is also inhibited by F-Asp. Collectively, these findings contribute to a better understanding of F-Asn utilization by Salmonella. IMPORTANCE Salmonella is able to utilize fructose-asparagine (F-Asn) as a nutrient. We recently reported that the disruption of a deglycase enzyme in the F-Asn utilization pathway inhibits the growth of Salmonella in mice and recognized this pathway as a novel and specific drug target. Here, we characterize the first step in the pathway wherein FraE hydrolyzes F-Asn to release NH4 + and F-Asp in the periplasm of the cell. A fraE mutant continues to grow slowly on F-Asn due to asparaginase activity encoded by ansB.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Salmonella FraE, an Asparaginase Homolog, Contributes to Fructose-Asparagine but Not Asparagine Utilization

et al. 2017

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“…For example, Salmonella Typhimurium infection induces asparagine deprivation by hydrolyzing asparagine via S . Typhimurium asparaginase, resulting in inhibition of mTOR signaling, Myc expression, T cell activation, and immune responses in the host ( 79 – 81 ). Using gas chromatography-mass spectrometry based metabolomics, ETEC was found to induce asparagine deprivation in the jejunum of piglets ( 51 ), but not in serum ( 9 ).…”

Section: Aa As Mediators Of Metabolic Cross Talk Between Host and Patmentioning

confidence: 99%

Amino Acids As Mediators of Metabolic Cross Talk between Host and Pathogen

et al. 2018

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The interaction between host and pathogen decidedly shapes the outcome of an infection, thus understanding this interaction is critical to the treatment of a pathogen-induced infection. Although research in this area of cell biology has yielded surprising findings regarding interactions between host and pathogen, understanding of the metabolic cross talk between host and pathogen is limited. At the site of infection, host and pathogen share similar or identical nutritional substrates and generate common metabolic products, thus metabolic cross talk between host and pathogen could profoundly affect the pathogenesis of an infection. In this review, we present results of a recent discovery of a metabolic interaction between host and pathogen from an amino acid (AA) metabolism-centric point of view. The host depends on AA metabolism to support defensive responses against pathogens, while the pathogens modulate AA metabolism for its own advantage. Some AA, such as arginine, asparagine, and tryptophan, are central points of competition between the host and pathogen. Thus, a better understanding of AA-mediated metabolic cross talk between host and pathogen will provide insight into fruitful therapeutic approaches to manipulate and prevent progression of an infection.

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“…A second example of a gastrointestinal bacterial protein that interferes with T cell metabolism comes from Salmonella enterica serovar Typhimurium, which has been reported to directly inhibit primary mouse T cells (55) and is thought to limit availability of asparagine to T cells (56). When assessing a number of cell surface-expressed molecules, no difference was noted in levels of CD69, CD25␣, CD44, and CD62L in cells infected with S. Typhimurium compared to uninfected controls.…”

Section: Proteins That Affect T Cell Activation and Proliferationmentioning

confidence: 99%

Direct Manipulation of T Lymphocytes by Proteins of Gastrointestinal Bacterial Pathogens

2018

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Gastrointestinal bacterial infection represents a significant threat to human health, as well as a burden on food animal production and welfare. Although there is advanced knowledge about the molecular mechanisms underlying pathogenesis, including the development of immune responses to these pathogens, gaps in knowledge persist. It is well established that gastrointestinal bacterial pathogens produce a myriad of proteins that affect the development and effectiveness of innate immune responses. However, relatively few proteins that directly affect lymphocytes responsible for humoral or cell-mediated immunity and memory have been identified. Here, we review factors produced by gastrointestinal bacterial pathogens that have direct T cell interactions and what is known about their functions and mechanisms of action. T cell-interacting bacterial proteins that have been identified to date mainly target three major T cell responses: activation and expansion, chemotaxis, or apoptosis. Further, the requirement for more focused studies to identify and understand additional mechanisms used by bacteria to directly affect the T cell immune response and how these may contribute to pathogenesis is highlighted. Increased knowledge in this area will help to drive development of better interventions in prevention and treatment of gastrointestinal bacterial infection.

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Contribution of Asparagine Catabolism to Salmonella Virulence

Cited by 13 publications

References 40 publications

Salmonella FraE, an Asparaginase Homolog, Contributes to Fructose-Asparagine but Not Asparagine Utilization

Salmonella FraE, an Asparaginase Homolog, Contributes to Fructose-Asparagine but Not Asparagine Utilization

Amino Acids As Mediators of Metabolic Cross Talk between Host and Pathogen

Direct Manipulation of T Lymphocytes by Proteins of Gastrointestinal Bacterial Pathogens

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