Coordinate Regulation of Bacterial Virulence Genes by a Novel Adenylate Cyclase-Dependent Signaling Pathway

Wolfgang, Matthew C.; Lee, Vincent T.; Gilmore, Meghan E.; Lory, Stephen

doi:10.1016/s1534-5807(03)00019-4

Cited by 351 publications

(597 citation statements)

References 40 publications

(6 reference statements)

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“…In addition to repressing the expression of pel genes, the RetS sensor positively controls the expression of the TTSS regulon. To determine whether the shared regulatory targets of LadS and RetS extend beyond the pel operon, we analyzed the expression of a transcriptional lacZ fusion to exoS, a TTSS effector gene coordinately regulated with the rest of the TTSS regulon (22). We observed a significant increase (2.5-fold) in the activity of the exoS promoter in a ladS mutant as compared with the PAK parental strain (Fig.…”

Section: Resultsmentioning

confidence: 96%

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Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes

Ventre

Goodman²,

Vallet-Gély³

et al. 2005

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

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378

461

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The opportunistic pathogen Pseudomonas aeruginosa is responsible for a wide range of acute and chronic infections. The transition to chronic infections is accompanied by physiological changes in the bacteria favoring formation of biofilm communities. Here we report the identification of LadS, a hybrid sensor kinase that controls the reciprocal expression of genes for type III secretion and biofilm-promoting polysaccharides. Domain organization of LadS and the range of LadS-controlled genes suggest that it counteracts the activities of another sensor kinase, RetS. These two pathways converge by controlling the transcription of a small regulatory RNA, RsmZ. This work identifies a previously undescribed signal transduction network in which the activities of signal-receiving sensor kinases LadS, RetS, and GacS regulate expression of virulence genes associated with acute or chronic infection by transcriptional and posttranscriptional mechanisms.biofilm ͉ pel genes ͉ small RNA ͉ two-component system ͉ type III secretion

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Section: Resultsmentioning

confidence: 96%

“…RNA was isolated, converted to cDNA, and labeled as described in ref. 22. Target hybridization to GeneChip P. aeruginosa Genome Arrays (Affymetrix), washing, and scanning were performed according to Affymetrix protocols.…”

Section: Methodsmentioning

confidence: 99%

Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes

Ventre

Goodman²,

Vallet-Gély³

et al. 2005

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

Self Cite

378

461

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“…We repeated the surface-sensing assay on agarose using isogenic mutants defective in cAMP production or in the Chp chemosensory regulon. In P. aeruginosa, the cyaB gene encodes the major adenylate cyclase (11). In the cyaB mutant, the PaQa reporter showed no increase in fluorescence upon surface contact (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the Chp system has been shown to regulate the level of the signaling molecule cAMP (9, 10), which in turn binds to the transcription factor Vfr (virulence factor regulator) to activate the transcription of more than 100 genes (11). Vfr regulates multiple virulence factors in P. aeruginosa, including the type II and III secretion systems and quorum sensing (11). Because these virulence pathways have a high metabolic cost, such complex regulatory networks are typically optimized to sense and respond to specific environments, thereby inducing virulence in the presence of a host.…”

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confidence: 99%

Type IV pili mechanochemically regulate virulence factors in Pseudomonas aeruginosa

Persat

Inclán

Engel

et al. 2015

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

343

398

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Bacteria have evolved a wide range of sensing systems to appropriately respond to environmental signals. Here we demonstrate that the opportunistic pathogen Pseudomonas aeruginosa detects contact with surfaces on short timescales using the mechanical activity of its type IV pili, a major surface adhesin. This signal transduction mechanism requires attachment of type IV pili to a solid surface, followed by pilus retraction and signal transduction through the Chp chemosensory system, a chemotaxis-like sensory system that regulates cAMP production and transcription of hundreds of genes, including key virulence factors. Like other chemotaxis pathways, pili-mediated surface sensing results in a transient response amplified by a positive feedback that increases type IV pili activity, thereby promoting long-term surface attachment that can stimulate additional virulence and biofilm-inducing pathways. The methyl-accepting chemotaxis protein-like chemosensor PilJ directly interacts with the major pilin subunit PilA. Our results thus support a mechanochemical model where a chemosensory system measures the mechanically induced conformational changes in stretched type IV pili. These findings demonstrate that P. aeruginosa not only uses type IV pili for surface-specific twitching motility, but also as a sensor regulating surface-induced gene expression and pathogenicity.surface sensing | mechanotransduction | type IV pili | virulence N umerous bacterial species exhibit a range of behaviors that are specific to life on surfaces. For many pathogens, surfacespecific phenotypes are often associated with virulent activity, because many infection strategies require contact with a host (1). For example, in Pseudomonas aeruginosa, the type III secretion system, which infects by injecting toxins, requires attachment of individual cells to host-cell membranes (2). The genetic pathways that regulate P. aeruginosa secretion systems have been well characterized (3), but the environmental signals that activate these pathways remain poorly defined (4). Given the requirement for host-cell contact for efficient infection, P. aeruginosa could leverage surface contact as a signal to properly activate and coordinate pathogenicity. Indeed, our laboratory recently demonstrated that prolonged association with a solid surface contributes to P. aeruginosa pathogenicity when bacteria and host cells are forced together (5). Here we address the fundamental question of how bacteria rapidly sense surface contact and transduce this input into a cellular response over short timescales.Surface-specific behaviors require intimate contact between cells and substrate. In P. aeruginosa, contact is mediated by several adhesins, particularly type IV pili (TFP). TFP are long, motorized fimbriae that also provide cells with surface-specific twitching motility and are essential to virulence and biofilm formation (6, 7). Successive TFP extension, attachment, and retraction promote intimate association with surfaces and motility along them. Because TFP dynamically int...

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“…Underlined sequences represent EcoRI and SpeI sites in the forward and reverse primers, respectively. Boldfaced sequence represents inclusion of an optimized ribosome binding site (Wolfgang et al, 2003). The 1692-bp ml1419c fragment was cloned into pJN105 (Newman & Fuqua, 1999) using the EcoRI and SpeI sites to generate pMRLB105.…”

Section: Methodsmentioning

confidence: 99%

Diguanylate cyclase activity of the Mycobacterium leprae T cell antigen ML1419c

et al. 2016

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The second messenger, bis-(3¢,5¢)-cyclic dimeric guanosine monophosphate (cyclic di-GMP), is involved in the control of multiple bacterial phenotypes, including those that impact host-pathogen interactions. Bioinformatics analyses predicted that Mycobacterium leprae, an obligate intracellular bacterium and the causative agent of leprosy, encodes three active diguanylate cyclases. In contrast, the related pathogen Mycobacterium tuberculosis encodes only a single diguanylate cyclase. One of the M. leprae unique diguanylate cyclases (ML1419c) was previously shown to be produced early during the course of leprosy. Thus, functional analysis of ML1419c was performed. The gene encoding ML1419c was cloned and expressed in Pseudomonas aeruginosa PAO1 to allow for assessment of cyclic di-GMP production and cyclic di-GMP-mediated phenotypes. Phenotypic studies revealed that ml1419c expression altered colony morphology, motility and biofilm formation of P. aeruginosa PAO1 in a manner consistent with increased cyclic di-GMP production. Direct measurement of cyclic di-GMP levels by liquid chromatography-mass spectrometry confirmed that ml1419c expression increased cyclic di-GMP production in P. aeruginosa PAO1 cultures in comparison to the vector control. The observed phenotypes and increased levels of cyclic di-GMP detected in P. aeruginosa expressing ml1419c could be abrogated by mutation of the active site in ML1419c. These studies demonstrated that ML1419c of M. leprae functions as diguanylate cyclase to synthesize cyclic di-GMP. Thus, this protein was renamed DgcA (Diguanylate cyclase A). These results also demonstrated the ability to use P. aeruginosa as a heterologous host for characterizing the function of proteins involved in the cyclic di-GMP pathway of a pathogen refractory to in vitro growth, M. leprae.

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Coordinate Regulation of Bacterial Virulence Genes by a Novel Adenylate Cyclase-Dependent Signaling Pathway

Cited by 351 publications

References 40 publications

Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes

Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes

Type IV pili mechanochemically regulate virulence factors in Pseudomonas aeruginosa

Diguanylate cyclase activity of the Mycobacterium leprae T cell antigen ML1419c

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