A glutamate-alanine-leucine (EAL) domain protein of Salmonella controls bacterial survival in mice, antioxidant defence and killing of macrophages: role of cyclic diGMP

Authors

  • Katherine B. Hisert,

    1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Programs in Immunology and Microbial Pathogenesis, Molecular Biology and/or Structural Biology/Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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  • Michael MacCoss,

    1. Department of Genome Sciences, University of Washington, Seattle, WA, USA.
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  • Michael U. Shiloh,

    1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Programs in Immunology and Microbial Pathogenesis, Molecular Biology and/or Structural Biology/Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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  • K. Heran Darwin,

    1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Programs in Immunology and Microbial Pathogenesis, Molecular Biology and/or Structural Biology/Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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  • Shaneen Singh,

    1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Programs in Immunology and Microbial Pathogenesis, Molecular Biology and/or Structural Biology/Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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  • Roger A. Jones,

    1. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
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  • Sabine Ehrt,

    1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Programs in Immunology and Microbial Pathogenesis, Molecular Biology and/or Structural Biology/Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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  • Zhaoying Zhang,

    1. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
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  • Barbara L. Gaffney,

    1. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
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  • Sheetal Gandotra,

    1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Programs in Immunology and Microbial Pathogenesis, Molecular Biology and/or Structural Biology/Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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  • David W. Holden,

    1. Center for Molecular Microbiology and Infection, Imperial College, London, UK.
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  • Diana Murray,

    1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Programs in Immunology and Microbial Pathogenesis, Molecular Biology and/or Structural Biology/Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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  • Carl Nathan

    Corresponding author
    1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Programs in Immunology and Microbial Pathogenesis, Molecular Biology and/or Structural Biology/Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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E-mail cnathan@med.cornell.edu; Tel. (+1) 212 746 6505; Fax (+1) 212 746 8587.

Summary

Signature-tagged transposon mutagenesis of Salmonella with differential recovery from wild-type and immunodeficient mice revealed that the gene here named cdgR[for c-diguanylate (c-diGMP) regulator] is required for the bacterium to resist host phagocyte oxidase in vivo. CdgR consists solely of a glutamate-alanine-leucine (EAL) domain, a predicted cyclic diGMP (c-diGMP) phosphodiesterase. Disruption of cdgR decreased bacterial resistance to hydrogen peroxide and accelerated bacterial killing of macrophages. An ultrasensitive assay revealed c-diGMP in wild-type Salmonella with increased levels in the CdgR-deficient mutant. Thus, besides its known role in regulating cellulose synthesis and biofilm formation, bacterial c-diGMP also regulates host–pathogen interactions involving antioxidant defence and cytotoxicity.

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