Coordinate Regulation and Sensory Transduction in the Control of Bacterial Virulence

Miller, Jeff F.; Mekalanos, John J.; Falkow, Stanley

doi:10.1126/science.2537530

Cited by 591 publications

(374 citation statements)

References 77 publications

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“…Mtb has evolved adaptive mechanisms, which promote survival within the infected host (Miller et al, 1989). Bacterial adaptation to the environment is often controlled by a two-component regulatory system (2CRS) comprising a sensor histidine kinase (HK) and a response regulator (RR).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of the two-component regulatory system senX3-regX3 in Mycobacterium tuberculosis

Rifat

Karakousis

2014

Microbiology

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The highly successful pathogen Mycobacterium tuberculosis (Mtb) has evolved strategies to adapt to various stress conditions, thus promoting survival within the infected host. The twocomponent regulatory system (2CRS) senX3-regX3, which has been implicated in the Mtb response to inorganic phosphate depletion, is believed to behave as an auto-regulatory bicistronic operon. Unlike other 2CRS, Mtb senX3-regX3 features an intergenic region (IR) containing several mycobacterium interspersed repetitive units (MIRU) of unknown function. In this study, we used a lacZ reporter system to study the promoter activity of the 59 untranslated region of senX3, and that of various numbers of MIRUs in the senX3-regX3 IR, during axenic Mtb growth in nutrient-rich broth, and upon exposure to growth-restricting conditions. Activity of the senX3 promoter was induced during phosphate depletion and nutrient starvation, and IR promoter activity under these conditions was directly proportional to the number of MIRUs present. Quantitative reverse transcriptase (qRT)-PCR analysis of exponentially growing Mtb revealed monocistronic transcription of senX3 and regX3, and, to a lesser degree, bicistronic transcription of the operon. In addition, we observed primarily monocistronic upregulation of regX3 during phosphate depletion of Mtb, which was confirmed by Northern analysis in wild-type Mtb and by RT-PCR in a senX3-disrupted mutant, while upregulation of regX3 in nutrient-starved Mtb was chiefly bicistronic. Our findings of differential regulation of senX3-regX3 highlight the potential regulatory role of MIRUs in the Mtb genome and provide insight into the regulatory mechanisms underlying Mtb adaptation to physiologically relevant conditions.

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Section: Introductionmentioning

confidence: 99%

Differential regulation of the two-component regulatory system senX3-regX3 in Mycobacterium tuberculosis

Rifat

Karakousis

2014

Microbiology

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“…This is true of invasins and the type III secretion system (T3SS) by which they are delivered into host cells. Together with various environmental conditions, nutrients are often included among factors that influence the pathogenicity of bacteria (Miller et al, 1989). The supply of the amino acid tryptophan is for example critical for intracellular pathogens such as chlamydiae (Beatty et al, 1994;Byrne et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Metabolic control through ornithine and uracil of epithelial cell invasion by Shigella flexneri

Durand

Björk

2009

Microbiology

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This paper shows that compounds in defined growth media strongly influence the expression of the effectors of virulence in the human invasive pathogen Shigella flexneri. Ornithine in conjunction with uracil reduces the haemolytic ability of wild-type cultures more than 20-fold and the expression of the type III secretion system more than 8-fold, as monitored by an mxiC : : lacZ transcriptional reporter. mxiC gene expression is further decreased by the presence of methionine or branched-chain amino acids (15-fold or 25-fold at least, respectively). Lysine and a few other aminated metabolites (cadaverine, homoserine and diaminopimelate) counteract the ornithinemediated inhibition of haemolytic activity and of the expression of a transcriptional activator virF reporter. The complete abolition of invasion of HeLa cells by wild-type bacteria by ornithine, uracil, methionine or branched-chain amino acids establishes that these metabolites are powerful effectors of virulence. These findings provide a direct connection between metabolism and virulence in S. flexneri. The inhibitory potential exhibited by the nutritional environment is stronger than temperature, the classical environmental effector of virulence. The implications and practical application of this finding in prophylaxis and treatment of shigellosis are discussed.

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“…For OspC, at least, this appears to be related to induction of specific protein synthesis by the spirochete in ticks following feeding upon a warm-blooded animal (43). Temperature-dependent differential expression of bacterial proteins that are involved in host infection has been observed in a number of other pathogenic bacteria (30). We sought to clone and characterize the ospE and ospF genes of B. burgdorferi B31 to better understand the genetic elements responsible for the temperature-induced differential expression of these and other genes.…”

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confidence: 99%

A family of genes located on four separate 32-kilobase circular plasmids in Borrelia burgdorferi B31

1996

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We have identified four loci in Borrelia burgdorferi B31 that contain open reading frames capable of encoding six proteins that are related to the antigenic proteins OspE and OspF. We have designated these proteins Erp, for OspEF-related protein, and named their respective genes erp. The erpA and erpB genes are linked, as are erpC and erpD, and the pairs probably constitute two operons. The erpG and erpH genes appear to be monocistronic. The ErpA and ErpC proteins are expressed by B. burgdorferi B31 in culture and are recognized by a polyclonal antiserum raised against the OspE protein of B. burgdorferi N40. The four erp loci are each located on different 32-kb circular plasmids that contain additional DNA sequences that are homologous to each other and to an 8.3-kb circular plasmid of B. burgdorferi sensu lato Ip21. All four 32-kb plasmids can be maintained within a single bacterium, which may provide a model for the study of plasmid replication and segregation in B. burgdorferi.Borrelia burgdorferi is a member of the order Spirochaetales, the spirochetes, an order that is phylogenetically and morphologically distinct from such well-characterized bacteria as Escherichia coli and Bacillus subtilis (8,24,34,35,53). B. burgdorferi bacteria naturally contain a wide variety of plasmids (4,13,25,40,42,45,47,54), yet nothing is known about the mechanisms by which plasmids are maintained in these bacteria. Several observations suggest that the small DNA species of B. burgdorferi and other spirochetes may be fundamentally different from the plasmids of other bacteria, the most significant being that there are linear plasmids in B. burgdorferi (4,5,7,13,22,23,42). Also, two B. burgdorferi genes involved in purine biosynthesis are located on a circular plasmid (29), which appears to be inconsistent with the classical definition of a plasmid as a nonessential extrachromosomal element. Other plasmids of B. burgdorferi appear to be capable of undergoing recombination to form multimeric plasmids (25, 31), and there have been reports of DNA sequences located on several different plasmids within the same bacterium (46,47,(54)(55)(56).B. burgdorferi is the causative agent of Lyme disease, an increasingly common ailment of humans and several other mammals (15,48). Infection of a mammal by B. burgdorferi is generally accompanied by the production of antibodies directed against a limited number of bacterial antigens (17,19,41,52), several of which have been identified as surface-exposed lipoproteins. At least three of these lipoproteins, OspC, OspE, and OspF, are differentially expressed by B. burgdorferi, being produced in greater quantities by cultured bacteria that are shifted from 23 to 32ЊC than by those maintained at the lower temperature (43, 49). For OspC, at least, this appears to be related to induction of specific protein synthesis by the spirochete in ticks following feeding upon a warm-blooded animal (43). Temperature-dependent differential expression of bacterial proteins that are involved in host infection has been o...

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Coordinate Regulation and Sensory Transduction in the Control of Bacterial Virulence

Cited by 591 publications

References 77 publications

Differential regulation of the two-component regulatory system senX3-regX3 in Mycobacterium tuberculosis

Differential regulation of the two-component regulatory system senX3-regX3 in Mycobacterium tuberculosis

Metabolic control through ornithine and uracil of epithelial cell invasion by Shigella flexneri

A family of genes located on four separate 32-kilobase circular plasmids in Borrelia burgdorferi B31

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