Hisert, K. B. et al. A glutamate-alanine-leucine (EAL) domain protein of Salmonella controls bacterial survival in mice, antioxidant defence and killing of macrophages: role of cyclic diGMP. Mol. Microbiol. 56, 1234-1245

Department of Microbiology and Immunology, Weill Medical College of Cornell University, and Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
Molecular Microbiology (Impact Factor: 4.42). 07/2005; 56(5):1234-45. DOI: 10.1111/j.1365-2958.2005.04632.x
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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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Available from: Michael U Shiloh, Oct 13, 2015
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    • "For instance, cellulose synthesis is affected by cyclic di-GMP levels in Gluconacetobacter xylinus (Ross et al., 1987), and biofilm formation and motility in Pseudomonas aeruginosa are regulated by cyclic di-GMP levels (Hickman et al., 2005). In both Vibrio cholerae (Tischler and Camilli, 2004) and Salmonella enterica serovar Typhimurium (Hisert et al., 2005), reduction of cyclic di-GMP concentration results in the induction of virulence genes. Cyclic di-GMP has also been shown to interact directly with riboswitch Cd1, where a decrease in cyclic di-GMP concentration increases the level of translation of the downstream flagella operon (Sudarsan et al., 2008). "
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    ABSTRACT: The stressosome complex regulates downstream effectors in response to environmental signals. In Bacillus subtilis, it activates the alternative sigma factor σ(B), leading to the upregulation of the general stress regulon. Herein, we characterize a stressosome-regulated biochemical pathway in Moorella thermoacetica. We show that the presumed sensor, MtR, and the scaffold, MtS, form a pseudo-icosahedral structure like that observed in B. subtilis. The N-terminal domain of MtR is structurally homologous to B. subtilis RsbR, despite low sequence identity. The affinity of the switch kinase, MtT, for MtS decreases following MtS phosphorylation and not because of structural reorganization. Dephosphorylation of MtS by the PP2C type phosphatase MtX permits the switch kinase to rebind the stressosome to reset the response. We also show that MtT regulates cyclic di-GMP biosynthesis through inhibition of a GG(D/E)EF-type diguanylate cyclase, demonstrating that secondary messenger levels are regulated by the stressosome.
    Structure 02/2012; 20(2):350-63. DOI:10.1016/j.str.2012.01.003 · 5.62 Impact Factor
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    • "On the contrary, in a S. enteriditis strain with deletion of all GG(D/E)EF domain proteins, expression of the catalytically inactive di-guanylate cyclase STM4551 was sufficient to restore virulence in the typhoid fever mouse model, a systemic infection model [26]. Also the EAL-domain like protein STM1344, which prevents Salmonella induced macrophage killing and mediates resistance to oxidative stress [25], neither metabolizes nor binds c-di-GMP [13]. In contrast, c-di-GMP signaling has been shown to modulate virulence in the enteric pathogen Vibrio cholerae, the causative agent of cholera [27]. "
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    ABSTRACT: Upon Salmonella enterica serovar Typhimurium infection of the gut, an early line of defense is the gastrointestinal epithelium which senses the pathogen and intrusion along the epithelial barrier is one of the first events towards disease. Recently, we showed that high intracellular amounts of the secondary messenger c-di-GMP in S. typhimurium inhibited invasion and abolished induction of a pro-inflammatory immune response in the colonic epithelial cell line HT-29 suggesting regulation of transition between biofilm formation and virulence by c-di-GMP in the intestine. Here we show that highly complex c-di-GMP signaling networks consisting of distinct groups of c-di-GMP synthesizing and degrading proteins modulate the virulence phenotypes invasion, IL-8 production and in vivo colonization in the streptomycin-treated mouse model implying a spatial and timely modulation of virulence properties in S. typhimurium by c-di-GMP signaling. Inhibition of the invasion and IL-8 induction phenotype by c-di-GMP (partially) requires the major biofilm activator CsgD and/or BcsA, the synthase for the extracellular matrix component cellulose. Inhibition of the invasion phenotype is associated with inhibition of secretion of the type three secretion system effector protein SipA, which requires c-di-GMP metabolizing proteins, but not their catalytic activity. Our findings show that c-di-GMP signaling is at least equally important in the regulation of Salmonella-host interaction as in the regulation of biofilm formation at ambient temperature.
    PLoS ONE 12/2011; 6(12):e28351. DOI:10.1371/journal.pone.0028351 · 3.23 Impact Factor
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    • "Cyclic di-GMP signalling can affect virtually almost all kind of virulence phenotypes including the overall in vivo virulence phenotype in animals and plants (Kulesekara et al., 2006; Ryan et al., 2007; Tamayo et al., 2007). Individual phenotypes, for example, interactions with host cells such as adherence to host cells, host cell invasion, cytotoxicity, intracellular infection, secretion of virulence factors and stimulation of immune response have been reported to be affected by cyclic di-GMP signalling (Hisert et al., 2005; Tischler and Camilli, 2005; Kulesekara et al., 2006; Lai et al., 2008; McWhirter et al., 2009; Kumagai et al., 2010; Lee et al., 2010a; Lamprokostopoulou et al., 2010; Sauer et al., 2011). Based on early investigations, the common view is that an acute infection process does not require cyclic di-GMP (Tamayo et al., 2007). "
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    ABSTRACT: The secondary messenger cyclic di-GMP coordinately regulates the transition between motility/sessility/virulence in bacterial populations and upon adaptation to novel habitats. Thereby, multiple independent regulatory circuits regulate a diversity of targets. This specific output response is surprising considering the diverse physiological processes regulated by this signalling molecule, which range from transcription to proteolysis and clearly demonstrates the presence of sophisticated developmental programmes in these so-called simple organisms.
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