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Virulence Gene Regulation in Bacteria

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Microbial Genetics and Genomics".

Deadline for manuscript submissions: closed (31 August 2016) | Viewed by 132803

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Special Issue Editor

Prof. Dr. Helen J. Wing

E-Mail Website1 Website2
Guest Editor

School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, NV 89154-4004, USA
Interests: mechanisms of bacterial pathogenesis; bacterial transcription and gene regulation; protein localization studies; bacterial motility and chemotaxis; outer membrane proteases; bacterial resistance to cationic antibacterial peptides; extra-host survival of bacterial pathogens

Special Issue Information

Dear Colleagues,

The precise control of virulence gene expression underpins the pathogenicity of many important bacterial pathogens. This regulatory control can be triggered by diverse stimuli including rising bacterial numbers, environmental stressors encountered in the host environment or even physical parameters, like direct contact between a bacterium and its host. Responding to these cues are suites of transcription factors and regulatory RNA molecules that function alone or in combination to up- or down-regulate the synthesis or longevity of transcripts. While the complexity of the regulatory networks and the variety of molecular mechanisms employed is impressive, their exquisite coordination is undoubtedly central to the physiology and the pathogenic nature of these bacteria. An improved understanding of these regulatory events has the potential to reveal processes unique to bacteria that can be exploited as novel drug targets. In a single issue of Genes in Fall of 2016, we would like to convey our current understanding of virulence gene regulation in bacteria by showcasing some of the best research from around the world. We welcome reviews and original articles in the area of transcriptional regulation and post-transcriptional control of bacterial virulence genes that are imparted by DNA binding proteins, small regulatory RNAs or even the transcripts themselves.

Assoc. Prof. Dr. Helen J. Wing
Guest Editor

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Keywords

Bacterial virulence
gene expression
transcriptional regulation
ribo-regulation
mRNA decay
subcellular localization of transcripts
quorum-sensing
two component regulatory systems
nucleoid structuring proteins
regulation of bacterial secretion
regulation of antibiotic resistance
post-transcriptional regulation
regulation of toxin production

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Published Papers (13 papers)

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Research

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2529 KiB

Open AccessArticle

Sibling sRNA RyfA1 Influences Shigella dysenteriae Pathogenesis

by Megan E. Fris, William H. Broach, Sarah E. Klim, Peter W. Coschigano, Ronan K. Carroll, Clayton C. Caswell and Erin R. Murphy

Genes 2017, 8(2), 50; https://doi.org/10.3390/genes8020050 - 26 Jan 2017

Cited by 11 | Viewed by 5798

Abstract

Small regulatory RNAs (sRNAs) of Shigella dysenteriae and other pathogens are vital for the regulation of virulence-associated genes and processes. Here, we characterize RyfA1, one member of a sibling pair of sRNAs produced by S. dysenteriae. Unlike its nearly identical sibling molecule, RyfA2, predicted to be encoded almost exclusively by non-pathogenic species, the presence of a gene encoding RyfA1, or a RyfA1-like molecule, is strongly correlated with virulence in a variety of enteropathogens. In S. dysenteriae, the overproduction of RyfA1 negatively impacts the virulence-associated process of cell-to-cell spread as well as the expression of ompC, a gene encoding a major outer membrane protein important for the pathogenesis of Shigella. Interestingly, the production of RyfA1 is controlled by a second sRNA, here termed RyfB1, the first incidence of one regulatory small RNA controlling another in S. dysenteriae or any Shigella species. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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2183 KiB

Open AccessArticle

Contribution of the RgfD Quorum Sensing Peptide to rgf Regulation and Host Cell Association in Group B Streptococcus

by Robert E. Parker, David Knupp, Rim Al Safadi, Agnѐs Rosenau and Shannon D. Manning

Genes 2017, 8(1), 23; https://doi.org/10.3390/genes8010023 - 6 Jan 2017

Cited by 10 | Viewed by 8172

Abstract

Streptococcus agalactiae (group B Streptococcus; GBS) is a common inhabitant of the genitourinary and/or gastrointestinal tract in up to 40% of healthy adults; however, this opportunistic pathogen is able to breach restrictive host barriers to cause disease and persist in harsh and changing conditions. This study sought to identify a role for quorum sensing, a form of cell to cell communication, in the regulation of the fibrinogen-binding (rgfBDAC) two-component system and the ability to associate with decidualized endometrial cells in vitro. To do this, we created a deletion in rgfD, which encodes the putative autoinducing peptide, in a GBS strain belonging to multilocus sequence type (ST)-17 and made comparisons to the wild type. Sequence variation in the rgf operon was detected in 40 clinical strains and a non-synonymous single nucleotide polymorphism was detected in rgfD in all of the ST-17 genomes that resulted in a truncation. Using qPCR, expression of rgf operon genes was significantly decreased in the ST-17 ΔrgfD mutant during exponential growth with the biggest difference (3.3-fold) occurring at higher cell densities. Association with decidualized endometrial cells was decreased 1.3-fold in the mutant relative to the wild type and rgfC expression was reduced 22-fold in ΔrgfD following exposure to the endometrial cells. Collectively, these data suggest that this putative quorum sensing molecule is important for attachment to human tissues and demonstrate a role for RgfD in GBS pathogenesis through regulation of rgfC. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Open AccessFeature PaperArticle

The Virulence Regulator Rns Activates the Expression of CS14 Pili

by Maria Del Rocio Bodero and George Patrick Munson

Genes 2016, 7(12), 120; https://doi.org/10.3390/genes7120120 - 8 Dec 2016

Cited by 7 | Viewed by 4241

Abstract

Although many viral and bacterial pathogens cause diarrhea, enterotoxigenic E. coli (ETEC) is one of the most frequently encountered in impoverished regions where it is estimated to kill between 300,000 and 700,000 children and infants annually. Critical ETEC virulence factors include pili which mediate the attachment of the pathogen to receptors in the intestinal lumen. In this study we show that the ETEC virulence regulator Rns positively regulates the expression of CS14 pili. Three Rns binding sites were identified upstream of the CS14 pilus promoter centered at −34.5, −80.5, and −155.5 relative to the Rns-dependent transcription start site. Mutagenesis of the promoter proximal site significantly decreased expression from the CS14 promoter. In contrast, the contribution of Rns bound at the promoter distal site was negligible and largely masked by occupancy of the promoter proximal site. Unexpectedly, Rns bound at the site centered at −80.5 had a slight but statistically significant inhibitory effect upon the pilin promoter. Nevertheless, this weak inhibitory effect was not sufficient to overcome the substantial promoter activation from Rns bound to the promoter proximal site. Thus, CS14 pili belong to a group of pili that depend upon Rns for their expression. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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2359 KiB

Open AccessArticle

OprD Repression upon Metal Treatment Requires the RNA Chaperone Hfq in Pseudomonas aeruginosa

by Verena Ducret, Manuel R. Gonzalez, Tiziana Scrignari and Karl Perron

Genes 2016, 7(10), 82; https://doi.org/10.3390/genes7100082 - 3 Oct 2016

Cited by 15 | Viewed by 7886

Abstract

The metal‐specific CzcRS two‐component system in Pseudomonas aeruginosa is involved in the repression of the OprD porin, causing in turn carbapenem antibiotic resistance in the presence of high zinc concentration. It has also been shown that CzcR is able to directly regulate the expression of multiple genes including virulence factors. CzcR is therefore an important regulator connecting (i) metal response, (ii) pathogenicity and (iii) antibiotic resistance in P. aeruginosa. Recent data have suggested that other regulators could negatively control oprD expression in the presence of zinc. Here we show that the RNA chaperone Hfq is a key factor acting independently of CzcR for the repression of oprD upon Zn treatment. Additionally, we found that an Hfq‐dependent mechanism is necessary for the localization of CzcR to the oprD promoter, mediating oprD transcriptional repression. Furthermore, in the presence of Cu, CopR, the transcriptional regulator of the CopRS two‐component system also requires Hfq for oprD repression. Altogether, these results suggest important roles for this RNA chaperone in the context of environment‐sensing and antibiotic resistance in P. aeruginosa. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Open AccessArticle

Presence of a Prophage Determines Temperature-Dependent Capsule Production in Streptococcus pyogenes

by Leslie Brown, Jeong-Ho Kim and Kyu Hong Cho

Genes 2016, 7(10), 74; https://doi.org/10.3390/genes7100074 - 24 Sep 2016

Cited by 5 | Viewed by 6050

Abstract

A hyaluronic acid capsule is a major virulence factor in the pathogenesis of Streptococcus pyogenes. It acts as an anti-phagocytic agent and adhesin to keratinocytes. The expression of the capsule is primarily regulated at the transcriptional level by the two-component regulatory system CovRS, in which CovR acts as a transcriptional repressor. The covRS genes are frequently mutated in many invasive strains, and a subset of the invasive CovRS mutants does not produce a detectable level of the capsule at 37 °C, but produces a significant amount of the capsule at sub-body temperatures. Here, we report that a prophage has a crucial role in this capsule thermoregulation. Passaging CovR-null strains showing capsule thermoregulation using a lab medium produced spontaneous mutants producing a significant amount of the capsule regardless of incubation temperature and this phenotypic change was caused by curing of a particular prophage. The lab strain HSC5 contains three prophages on the chromosome, and only ΦHSC5.3 was cured in all spontaneous mutants. This result indicates that the prophage ΦHSC5.3 plays a crucial role in capsule thermoregulation, most likely by repressing capsule production at 37 °C. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Review

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479 KiB

Open AccessReview

Burkholderia cepacia Complex Regulation of Virulence Gene Expression: A Review

by Sílvia A. Sousa, Joana R. Feliciano, Tiago Pita, Soraia I. Guerreiro and Jorge H. Leitão

Genes 2017, 8(1), 43; https://doi.org/10.3390/genes8010043 - 19 Jan 2017

Cited by 35 | Viewed by 9988

Abstract

Burkholderia cepacia complex (Bcc) bacteria emerged as opportunistic pathogens in cystic fibrosis and immunocompromised patients. Their eradication is very difficult due to the high level of intrinsic resistance to clinically relevant antibiotics. Bcc bacteria have large and complex genomes, composed of two to four replicons, with variable numbers of insertion sequences. The complexity of Bcc genomes confers a high genomic plasticity to these bacteria, allowing their adaptation and survival to diverse habitats, including the human host. In this work, we review results from recent studies using omics approaches to elucidate in vivo adaptive strategies and virulence gene regulation expression of Bcc bacteria when infecting the human host or subject to conditions mimicking the stressful environment of the cystic fibrosis lung. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Open AccessReview

The Complex Relationship between Virulence and Antibiotic Resistance

by Meredith Schroeder, Benjamin D. Brooks and Amanda E. Brooks

Genes 2017, 8(1), 39; https://doi.org/10.3390/genes8010039 - 18 Jan 2017

Cited by 210 | Viewed by 21671

Abstract

Antibiotic resistance, prompted by the overuse of antimicrobial agents, may arise from a variety of mechanisms, particularly horizontal gene transfer of virulence and antibiotic resistance genes, which is often facilitated by biofilm formation. The importance of phenotypic changes seen in a biofilm, which lead to genotypic alterations, cannot be overstated. Irrespective of if the biofilm is single microbe or polymicrobial, bacteria, protected within a biofilm from the external environment, communicate through signal transduction pathways (e.g., quorum sensing or two-component systems), leading to global changes in gene expression, enhancing virulence, and expediting the acquisition of antibiotic resistance. Thus, one must examine a genetic change in virulence and resistance not only in the context of the biofilm but also as inextricably linked pathologies. Observationally, it is clear that increased virulence and the advent of antibiotic resistance often arise almost simultaneously; however, their genetic connection has been relatively ignored. Although the complexities of genetic regulation in a multispecies community may obscure a causative relationship, uncovering key genetic interactions between virulence and resistance in biofilm bacteria is essential to identifying new druggable targets, ultimately providing a drug discovery and development pathway to improve treatment options for chronic and recurring infection. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Open AccessReview

Quorum Sensing Regulation of Competence and Bacteriocins in Streptococcus pneumoniae and mutans

by Erin Shanker and Michael J. Federle

Genes 2017, 8(1), 15; https://doi.org/10.3390/genes8010015 - 5 Jan 2017

Cited by 127 | Viewed by 16703

Abstract

The human pathogens Streptococcus pneumoniae and Streptococcus mutans have both evolved complex quorum sensing (QS) systems that regulate the production of bacteriocins and the entry into the competent state, a requirement for natural transformation. Natural transformation provides bacteria with a mechanism to repair damaged genes or as a source of new advantageous traits. In S. pneumoniae, the competence pathway is controlled by the two-component signal transduction pathway ComCDE, which directly regulates SigX, the alternative sigma factor required for the initiation into competence. Over the past two decades, effectors of cellular killing (i.e., fratricides) have been recognized as important targets of the pneumococcal competence QS pathway. Recently, direct interactions between the ComCDE and the paralogous BlpRH pathway, regulating bacteriocin production, were identified, further strengthening the interconnections between these two QS systems. Interestingly, a similar theme is being revealed in S. mutans, the primary etiological agent of dental caries. This review compares the relationship between the bacteriocin and the competence QS pathways in both S. pneumoniae and S. mutans, and hopes to provide clues to regulatory pathways across the genus Streptococcus as a potential tool to efficiently investigate putative competence pathways in nontransformable streptococci. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Open AccessReview

Genetic Regulation of Virulence and Antibiotic Resistance in Acinetobacter baumannii

by Carsten Kröger, Stefani C. Kary, Kristina Schauer and Andrew D. S. Cameron

Genes 2017, 8(1), 12; https://doi.org/10.3390/genes8010012 - 28 Dec 2016

Cited by 77 | Viewed by 13911

Abstract

Multidrug resistant microorganisms are forecast to become the single biggest challenge to medical care in the 21st century. Over the last decades, members of the genus Acinetobacter have emerged as bacterial opportunistic pathogens, in particular as challenging nosocomial pathogens because of the rapid evolution of antimicrobial resistances. Although we lack fundamental biological insight into virulence mechanisms, an increasing number of researchers are working to identify virulence factors and to study antibiotic resistance. Here, we review current knowledge regarding the regulation of virulence genes and antibiotic resistance in Acinetobacter baumannii. A survey of the two-component systems AdeRS, BaeSR, GacSA and PmrAB explains how each contributes to antibiotic resistance and virulence gene expression, while BfmRS regulates cell envelope structures important for pathogen persistence. A. baumannii uses the transcription factors Fur and Zur to sense iron or zinc depletion and upregulate genes for metal scavenging as a critical survival tool in an animal host. Quorum sensing, nucleoid-associated proteins, and non-classical transcription factors such as AtfA and small regulatory RNAs are discussed in the context of virulence and antibiotic resistance. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Open AccessReview

Regulation of Pseudomonas aeruginosa Virulence by Distinct Iron Sources

by Alexandria A. Reinhart and Amanda G. Oglesby-Sherrouse

Genes 2016, 7(12), 126; https://doi.org/10.3390/genes7120126 - 14 Dec 2016

Cited by 46 | Viewed by 10312

Abstract

Pseudomonas aeruginosa is a ubiquitous environmental bacterium and versatile opportunistic pathogen. Like most other organisms, P. aeruginosa requires iron for survival, yet iron rapidly reacts with oxygen and water to form stable ferric (FeIII) oxides and hydroxides, limiting its availability to living organisms. During infection, iron is also sequestered by the host innate immune system, further limiting its availability. P. aeruginosa’s capacity to cause disease in diverse host environments is due to its ability to scavenge iron from a variety of host iron sources. Work over the past two decades has further shown that different iron sources can affect the expression of distinct virulence traits. This review discusses how the individual components of P. aeruginosa’s iron regulatory network allow this opportunist to adapt to a multitude of host environments during infection. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Open AccessReview

H-NS, Its Family Members and Their Regulation of Virulence Genes in Shigella Species

by Michael A. Picker and Helen J. Wing

Genes 2016, 7(12), 112; https://doi.org/10.3390/genes7120112 - 1 Dec 2016

Cited by 22 | Viewed by 7489

Abstract

The histone-like nucleoid structuring protein (H-NS) has played a key role in shaping the evolution of Shigella spp., and provides the backdrop to the regulatory cascade that controls virulence by silencing many genes found on the large virulence plasmid. H-NS and its paralogue StpA are present in all four Shigella spp., but a second H-NS paralogue, Sfh, is found in the Shigella flexneri type strain 2457T, which is routinely used in studies of Shigella pathogenesis. While StpA and Sfh have been proposed to serve as “molecular backups” for H-NS, the apparent redundancy of these proteins is questioned by in vitro studies and work done in Escherichia coli. In this review, we describe the current understanding of the regulatory activities of the H-NS family members, the challenges associated with studying these proteins and their role in the regulation of virulence genes in Shigella. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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Open AccessReview

The SaeRS Two‐Component System of Staphylococcus aureus

by Qian Liu, Won‐Sik Yeo and Taeok Bae

Genes 2016, 7(10), 81; https://doi.org/10.3390/genes7100081 - 3 Oct 2016

Cited by 147 | Viewed by 14385

Abstract

In the Gram‐positive pathogenic bacterium Staphylococcus aureus, the SaeRS twocomponent system (TCS) plays a major role in controlling the production of over 20 virulence factors including hemolysins, leukocidins, superantigens, surface proteins, and proteases. The SaeRS TCS is composed of the sensor histidine kinase SaeS, response regulator SaeR, and two auxiliary proteins SaeP and SaeQ. Since its discovery in 1994, the sae locus has been studied extensively, and its contributions to staphylococcal virulence and pathogenesis have been well documented and understood; however, the molecular mechanism by which the SaeRS TCS receives and processes cognate signals is not. In this article, therefore, we review the literature focusing on the signaling mechanism and its interaction with other global regulators. Full article

(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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