RpiR Homologues May Link Staphylococcus aureus RNAIII Synthesis and Pentose Phosphate Pathway Regulation

Zhu, Yefei; Nandakumar, Renu; Sadykov, Marat R.; Madayiputhiya, Nandakumar; Luong, Thanh T.; Gaupp, R.; Lee, Chia Y.; Somerville, Greg A.

doi:10.1128/jb.05930-11

Cited by 49 publications

(73 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The RpiR family of metabolite-responsive regulators functions to link central metabolism to virulence determinant biosynthesis in S. aureus (3). This linkage is critical because it connects the availability of the central metabolism generated bio-synthetic intermediates (e.g., ␣-ketoglutarate and glucose-6-phosphate) with the synthesis of virulence determinants.…”

Section: Discussionmentioning

confidence: 99%

“…As examples, the carbon catabolite protein A (CcpA) responds to glucose-associated metabolic signals (54), whereas CodY responds to GTP and branched-chain amino acids (50,55). As mentioned, we recently identified a putative metabolite-responsive family of regulators in S. aureus, RpiR, which contain a DNA-binding helix-turn-helix motif and a sugar isomerase binding domain (3). Inactivation of the rpiRc gene in S. aureus strain UAMS-1 dramatically increased the transcription and/or stability of RNAIII (3).…”

mentioning

confidence: 99%

“…During colonization and infection of a host, S. aureus must adapt to rapidly changing environmental and nutritional conditions by coordinating the transcription and translation of physiologic and virulence genes (2). To coordinately control these cellular processes, S. aureus has evolved or acquired a network of regulators such as the recently identified family of proteins, RpiR, that affect pentose phosphate pathway activity and virulence determinant synthesis (3).…”

mentioning

confidence: 99%

See 2 more Smart Citations

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus

et al. 2016

Self Cite

View full text Add to dashboard Cite

fIn Staphylococcus aureus, metabolism is intimately linked with virulence determinant biosynthesis, and several metabolite-responsive regulators have been reported to mediate this linkage. S. aureus possesses at least three members of the RpiR family of transcriptional regulators. Of the three RpiR homologs, RpiRc is a potential regulator of the pentose phosphate pathway, which also regulates RNAIII levels. RNAIII is the regulatory RNA of the agr quorum-sensing system that controls virulence determinant synthesis. The effect of RpiRc on RNAIII likely involves other regulators, as the regulators that bind the RNAIII promoter have been intensely studied. To determine which regulators might bridge the gap between RpiRc and RNAIII, sarA, sigB, mgrA, and acnA mutations were introduced into an rpiRc mutant background, and the effects on RNAIII were determined. Additionally, phenotypic and genotypic differences were examined in the single and double mutant strains, and the virulence of select strains was examined using two different murine infection models. The data suggest that RpiRc affects RNAIII transcription and the synthesis of virulence determinants in concert with B , SarA, and the bacterial metabolic status to negatively affect virulence. Staphylococcus aureus is a major human pathogen causing a diverse range of infections, from superficial skin and wound infections to life-threatening diseases such as bacteremia, endocarditis, osteomyelitis, deep tissue abscesses, or pneumonia (1). The pathogenicity of S. aureus is due in part to its ability to produce a large number of virulence determinants, including secreted proteins (e.g., toxins and proteases), cell wall-associated proteins (e.g., protein A and fibronectin binding proteins), and extracellular polysaccharides (i.e., capsule and polysaccharide intercellular adhesion). During colonization and infection of a host, S. aureus must adapt to rapidly changing environmental and nutritional conditions by coordinating the transcription and translation of physiologic and virulence genes (2). To coordinately control these cellular processes, S. aureus has evolved or acquired a network of regulators such as the recently identified family of proteins, RpiR, that affect pentose phosphate pathway activity and virulence determinant synthesis (3).Central to the regulatory network is the accessory gene regulator (Agr) system, a regulator of virulence determinant synthesis that responds to the bacterial population density (4). The agr locus consists of two divergent transcriptional units, RNAII and RNAIII, driven by the P2 and P3 promoters, respectively. RNAII comprises the agrBDCA operon, of which the agrBD gene products are involved in the synthesis, transport, and maturation of an autoinducing peptide (AIP). As the cell density increases, AIP accumulates in the extracellular milieu and when a threshold is achieved the two-component system AgrCA responds by activating transcription of both P2 and P3 promoters. The P3 promoter drives transcription of RNAIII, which is the re...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Another strongly negatively selected putative transcriptional regulator, RpiR, is encoded by bpsl0629. RpiR has been demonstrated to regulate various virulence factors of Staphylococcus aureus, suggesting that this could be another conserved regulatory gene required for in vivo virulence (36). bpsl1728 and bpss1528 both encode predicted secreted proteins, with bpss1528 encoding a type III secretion system secreted protein and the bpsl1728 product showing homology to a secreted outer membrane porin from Bordetella pertussis.…”

Section: Resultsmentioning

confidence: 99%

Characterization of New Virulence Factors Involved in the Intracellular Growth and Survival of Burkholderia pseudomallei

et al. 2016

View full text Add to dashboard Cite

dBurkholderia pseudomallei, the causative agent of melioidosis, has complex and poorly understood extracellular and intracellular lifestyles. We used transposon-directed insertion site sequencing (TraDIS) to retrospectively analyze a transposon library that had previously been screened through a BALB/c mouse model to identify genes important for growth and survival in vivo. This allowed us to identify the insertion sites and phenotypes of negatively selected mutants that were previously overlooked due to technical constraints. All 23 unique genes identified in the original screen were confirmed by TraDIS, and an additional 105 mutants with various degrees of attenuation in vivo were identified. Five of the newly identified genes were chosen for further characterization, and clean, unmarked bpsl2248, tex, rpiR, bpsl1728, and bpss1528 deletion mutants were constructed from the wild-type strain K96243. Each of these mutants was tested in vitro and in vivo to confirm their attenuated phenotypes and investigate the nature of the attenuation. Our results confirm that we have identified new genes important to in vivo virulence with roles in different stages of B. pseudomallei pathogenesis, including extracellular and intracellular survival. Of particular interest, deletion of the transcription accessory protein Tex was shown to be highly attenuating, and the tex mutant was capable of providing protective immunity against challenge with wild-type B. pseudomallei, suggesting that the genes identified in our TraDIS screen have the potential to be investigated as live vaccine candidates. Burkholderia pseudomallei is a Gram-negative, motile saprophytic bacterium that is the causative agent of melioidosis. This emerging human pathogen is endemic to the soil and water of tropical areas, including Thailand, Singapore, and northern Australia, and can cause infection through contact with broken skin or through ingestion or inhalation of the bacterium (1). The resulting disease can manifest as a localized skin ulcer or can progress to a systemic infection that is associated with mortality rates as high as 50% in some regions of endemicity (2). There is currently no licensed vaccine against B. pseudomallei available, and it is highly resistant to most antibiotics, severely limiting treatment options (3). Due to the virulent nature of the pathogen, potential for aerosol transmission, and lack of therapeutic options, B. pseudomallei is listed as a Tier 1 bioterrorism threat by the Centers for Disease Control and Prevention (4).B. pseudomallei is a facultative intracellular pathogen capable of invading and replicating within both epithelial cells and macrophages (5). While B. pseudomallei is capable of extracellular growth and survival and is highly resistant to complement-mediated killing in human sera, intracellular growth is essential for virulence (2, 6). When B. pseudomallei enters the host cell, either through phagocytosis or by inducing its own uptake into nonphagocytic cells, it is able to escape from the phagosome or endocyt...

show abstract

“…Other members of the RpiR family of transcriptional regulators are most commonly associated with the repression of carbohydrate metabolism genes (24,25,37,38). Two RpiR family homologs in Staphylococcus aureus have been demonstrated to regulate pentose phosphate pathway enzymes in addition to virulence genes via regulation of RNAIII synthesis (41). This family of regulatory proteins may act as a checkpoint to virulence factor production within the cell.…”

Section: Discussionmentioning

confidence: 99%

QapR (PA5506) Represses an Operon That Negatively Affects the Pseudomonas Quinolone Signal in Pseudomonas aeruginosa

2013

View full text Add to dashboard Cite

Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that can cause disease in varied sites within the human body and is a significant source of morbidity and mortality in those afflicted with cystic fibrosis. P. aeruginosa is able to coordinate group behaviors, such as virulence factor production, through the process of cell-to-cell signaling. There are three intercellular signaling systems employed by P. aeruginosa, and one of these systems utilizes the small molecule 2-heptyl-3-hydroxy-4-quinolone (Pseudomonas quinolone signal [PQS]). PQS is required for virulence in multiple infection models and has been found in the lungs of cystic fibrosis patients colonized by P. aeruginosa. In this study, we have identified an RpiR family transcriptional regulator, QapR, which is an autoregulatory repressor. We found that mutation of qapR caused overexpression of the qapR operon. We characterized the qapR operon to show that it contains genes qapR, PA5507, PA5508, and PA5509 and that QapR directly controls the transcription of these genes in a negative manner. We also show that derepression of this operon greatly reduces PQS concentration in P. aeruginosa. Our results suggest that qapR affects PQS concentration by repressing an enzymatic pathway that acts on PQS or a PQS precursor to lower the PQS concentration. We believe that this operon comprises a novel mechanism to regulate PQS concentration in P. aeruginosa. Pseudomonas aeruginosa is a ubiquitous, Gram-negative bacterium that can infect a broad range of hosts, including insects, plants, and animals (1-3). This prevalent opportunistic pathogen is frequently acquired in the nosocomial setting and causes intractable infections in the lungs of cystic fibrosis patients (4-6). The ability of this organism to colonize and cause disease is tied to its vast array of virulence factors, such as pyocyanin, alkaline protease, hydrogen cyanide, elastase, and rhamnolipid, which are produced in response to intercellular signals (7-10).There are three cell-to-cell signaling systems that P. aeruginosa utilizes to coordinate expression of numerous genes for metabolic processes and virulence factor production (7, 9). The lasRI signaling system is at the top of the cell-to-cell signaling hierarchy and positively regulates the rhlRI and quinolone signaling systems (11). The las and rhl quorum sensing systems produce and respond to the acyl-homoserine lactone signals N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C 12 -HSL) and N-butyryl-L-homoserine lactone (C 4 -HSL), respectively (12, 13). The other cell-to-cell signaling system functions through the quinolone compound 2-heptyl-3-hydroxy-4-quinolone (the Pseudomonas quinolone signal [PQS]) (14). Production of PQS is mediated by the products of the pqsABCD operon and the pqsH gene and occurs through the condensation of the precursors anthranilate and ␤-ketodecanoic acid (15). PQS then interacts with and activates PqsR, which positively controls expression of the PQS biosynthetic operon (pqsABCDE) in an autoregulatory loop...

show abstract

RpiR Homologues May Link Staphylococcus aureus RNAIII Synthesis and Pentose Phosphate Pathway Regulation

Cited by 49 publications

References 47 publications

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus

Characterization of New Virulence Factors Involved in the Intracellular Growth and Survival of Burkholderia pseudomallei

QapR (PA5506) Represses an Operon That Negatively Affects the Pseudomonas Quinolone Signal in Pseudomonas aeruginosa

Contact Info

Product

Resources

About