CdpA Is a
            <i>Burkholderia pseudomallei</i>
            Cyclic di-GMP Phosphodiesterase Involved in Autoaggregation, Flagellum Synthesis, Motility, Biofilm Formation, Cell Invasion, and Cytotoxicity

Lee, Hwee Siang; Gu, Feiyu; Ching, Shi Min; Lam, Yulin; Chua, Kim Lee

doi:10.1128/iai.00446-09

Cited by 71 publications

(90 citation statements)

References 46 publications

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“…In line with this observation, the virulence of a flagellar gene deletion mutant was also partially impaired. A nonflagellated CdpA PDE mutant of Burkholderia pseudomallei was less cytotoxic to THP-1 human macrophage cells and showed reduced invasion of A549 human lung epithelial cells (337). Since flagellar expression is required for invasion and cytotoxicity of B. pseudomallei (344), the lack of flagellum expression in the cdpA mutant most likely contributed to the downregulation of virulence.…”

Section: Cyclic Di-gmp and Virulencementioning

confidence: 99%

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Römling

Galperin

Gomelsky

2013

Microbiol Mol Biol Rev

1,471

1,698

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SUMMARY Twenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger.

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Section: Cyclic Di-gmp and Virulencementioning

confidence: 99%

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Römling

Galperin

Gomelsky

2013

Microbiol Mol Biol Rev

1,471

1,698

View full text Add to dashboard Cite

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“…14). Bioinformatics analysis of the cyclic di-GMP metabolic genes in B. pseudomallei strain KHW was not reported, so it is impossible to predict whether this analysis generally describes the role of cyclic di-GMP metabolism in B. pseudomallei without additional studies (26). It is also relevant to consider expanding analyses to include additional cyclic di-GMP-associated genes for this organism in order to better understand the overall complexity of the cyclic di-GMP signaling network.…”

Section: Importancementioning

confidence: 99%

Thermoregulation of Biofilm Formation in Burkholderia pseudomallei Is Disrupted by Mutation of a Putative Diguanylate Cyclase

et al. 2017

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Burkholderia pseudomallei, a tier 1 select agent and the etiological agent of melioidosis, transitions from soil and aquatic environments to infect a variety of vertebrate and invertebrate hosts. During the transition from an environmental saprophyte to a mammalian pathogen, B. pseudomallei encounters and responds to rapidly changing environmental conditions. Environmental sensing systems that control cellular levels of cyclic di-GMP promote pathogen survival in diverse environments. Cyclic di-GMP controls biofilm production, virulence factors, and motility in many bacteria. This study is an evaluation of cyclic di-GMP-associated genes that are predicted to metabolize and interact with cyclic di-GMP as identified from the annotated genome of B. pseudomallei 1026b. Mutants containing transposon disruptions in each of these genes were characterized for biofilm formation and motility at two temperatures that reflect conditions that the bacteria encounter in the environment and during the infection of a mammalian host. Mutants with transposon insertions in a known phosphodiesterase (cdpA) and a predicted hydrolase (Bp1026b_I2285) gene exhibited decreased motility regardless of temperature. In contrast, the phenotypes exhibited by mutants with transposon insertion mutations in a predicted diguanylate cyclase gene (Bp1026b_II2523) were strikingly influenced by temperature and were dependent on a conserved GG(D/E)EF motif. The transposon insertion mutant exhibited enhanced biofilm formation at 37°C but impaired biofilm formation at 30°C. These studies illustrate the importance of studying behaviors regulated by cyclic di-GMP under varied environmental conditions in order to better understand cyclic di-GMP signaling in bacterial pathogens.IMPORTANCE This report evaluates predicted cyclic di-GMP binding and metabolic proteins from Burkholderia pseudomallei 1026b, a tier 1 select agent and the etiologic agent of melioidosis. Transposon insertion mutants with disruptions in each of the genes encoding these predicted proteins were characterized in order to identify key components of the B. pseudomallei cyclic di-GMP-signaling network. A predicted hydrolase and a phosphodiesterase that modulate swimming motility were identified, in addition to a diguanylate cyclase that modulates biofilm formation and motility in response to temperature. These studies warrant further evaluation of the contribution of cyclic di-GMP to melioidosis in the context of pathogen acquisition from environmental reservoirs and subsequent colonization, dissemination, and persistence within the host.

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“…The c-di-GMP signaling molecule negatively regulates the flagellar motility of a large number of bacteria by diverse mechanisms, including transcriptional, posttranscriptional, and posttranslational control (36)(37)(38)(39)(40)(41)(42)(43)(44). In C. difficile, regulation of motility by c-di-GMP likely occurs through a direct effect of c-di-GMP on the expression of a putative large flagellar operon, the flgB operon, via a c-di-GMP riboswitch (45).…”

mentioning

confidence: 99%

The Second Messenger Cyclic Di-GMP Regulates Clostridium difficile Toxin Production by Controlling Expression of sigD

et al. 2013

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The Gram-positive obligate anaerobe Clostridium difficile causes potentially fatal intestinal diseases. How this organism regulates virulence gene expression is poorly understood. In many bacterial species, the second messenger cyclic di-GMP (c-di-GMP) negatively regulates flagellar motility and, in some cases, virulence. c-di-GMP was previously shown to repress motility of C. difficile. Recent evidence indicates that flagellar gene expression is tightly linked with expression of the genes encoding the two C. difficile toxins TcdA and TcdB, which are key virulence factors for this pathogen. Here, the effect of c-di-GMP on expression of the toxin genes tcdA and tcdB was determined, and the mechanism connecting flagellar and toxin gene expressions was examined. In C. difficile, increasing c-di-GMP levels reduced the expression levels of tcdA and tcdB, as well as that of tcdR, which encodes an alternative sigma factor that activates tcdA and tcdB expression. We hypothesized that the C. difficile orthologue of the flagellar alternative sigma factor SigD (FliA; 28 ) mediates regulation of toxin gene expression in response to c-di-GMP. Indeed, ectopic expression of sigD in C. difficile resulted in increased expression levels of tcdR, tcdA, and tcdB. Furthermore, sigD expression enhanced toxin production and increased the cytopathic effect of C. difficile on cultured fibroblasts. Finally, evidence is provided that SigD directly activates tcdR expression and that SigD cannot activate tcdA or tcdB expression independent of TcdR. Taken together, these data suggest that SigD positively regulates toxin genes in C. difficile and that c-di-GMP can inhibit both motility and toxin production via SigD, making this signaling molecule a key virulence gene regulator in C. difficile.

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CdpA Is a Burkholderia pseudomallei Cyclic di-GMP Phosphodiesterase Involved in Autoaggregation, Flagellum Synthesis, Motility, Biofilm Formation, Cell Invasion, and Cytotoxicity

Cited by 71 publications

References 46 publications

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Thermoregulation of Biofilm Formation in Burkholderia pseudomallei Is Disrupted by Mutation of a Putative Diguanylate Cyclase

The Second Messenger Cyclic Di-GMP Regulates Clostridium difficile Toxin Production by Controlling Expression of sigD

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