Bacterial pathogens employ a number of genetic strategies to cause infection and, occasionally, disease in their hosts. Many of these virulence factors and their regulatory elements can be divided into a smaller number of groups based on the conservation of similar mechanisms. These common themes are found throughout bacterial virulence factors. For example, there are only a few general types of toxins, despite a large number of host targets. Similarly, there are only a few conserved ways to build the bacterial pilus and nonpilus adhesins used by pathogens to adhere to host substrates. Bacterial entry into host cells (invasion) is a complex mechanism. However, several common invasion themes exist in diverse microorganisms. Similarly, once inside a host cell, pathogens have a limited number of ways to ensure their survival, whether remaining within a host vacuole or by escaping into the cytoplasm. Avoidance of the host immune defenses is key to the success of a pathogen. Several common themes again are employed, including antigenic variation, camouflage by binding host molecules, and enzymatic degradation of host immune components. Most virulence factors are found on the bacterial surface or secreted into their immediate environment, yet virulence factors operate through a relatively small number of microbial secretion systems. The expression of bacterial pathogenicity is dependent upon complex regulatory circuits. However, pathogens use only a small number of biochemical families to express distinct functional factors at the appropriate time that causes infection. Finally, virulence factors maintained on mobile genetic elements and pathogenicity islands ensure that new strains of pathogens evolve constantly. Comprehension of these common themes in microbial pathogenicity is critical to the understanding and study of bacterial virulence mechanisms and to the development of new "anti-virulence" agents, which are so desperately needed to replace antibiotics.

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Common themes in microbial pathogenicity revisited.

▪ Abstract Xenorhabdus and Photorhabdus spp. are gram negative gamma proteobacteria that form entomopathogenic symbioses with soil nematodes. They undergo a complex life cycle that involves a symbiotic stage, in which the bacteria are carried in the gut of the nematodes, and a pathogenic stage, in which susceptible insect prey are killed by the combined action of the nematode and the bacteria. Both bacteria produce antibiotics, intracellular protein crystals, and numerous other products. These traits change in phase variants, which arise when the bacteria are maintained under stationary phase conditions in the laboratory. Molecular biological studies suggest that Xenorhabdus and Photorhabdus spp. may serve as valuable model systems for studying signal transduction and transcriptional and posttranscriptional regulation of gene expression. Such studies also indicate that these bacterial groups, which had been previously considered to be very similar, may actually be quite different at the molecular level.

XENORHABDUS AND PHOTORHABDUS SPP.: Bugs That Kill Bugs

Quorum sensing is a cell-to-cell signaling mechanism in which bacteria respond to hormone-like molecules called autoinducers (AIs). The AI-3 quorum-sensing system is also involved in interkingdom signaling with the eukaryotic hormones epinephrine/norepinephrine. This signaling activates transcription of virulence genes in enterohemorrhagic Escherichia coli O157:H7. However, this signaling system has never been shown to be involved in virulence in vivo, and the bacterial receptor for these signals had not been identified. Here, we show that the QseC sensor kinase is a bacterial receptor for the host epinephrine/norepinephrine and the AI-3 produced by the gastrointestinal microbial flora. We also found that an α-adrenergic antagonist can specifically block the QseC response to these signals. Furthermore, we demonstrated that a qseC mutant is attenuated for virulence in a rabbit animal model, underscoring the importance of this signaling system in virulence in vivo. Finally, an in silico search found that the periplasmic sensing domain of QseC is conserved among several bacterial species. Thus, QseC is a bacterial adrenergic receptor that activates virulence genes in response to interkingdom cross-signaling. We anticipate that these studies will be a starting point in understanding bacterial–host hormone signaling at the biochemical level. Given the role that this system plays in bacterial virulence, further characterization of this unique signaling mechanism may be important for developing novel classes of antimicrobials.

https://www.pnas.org/content/pnas/103/27/10420.full.pdf

The QseC sensor kinase: A bacterial adrenergic receptor

1. Introduction: From Physiology to DNA and Back.- 2. RNA Chain Initiation and Promoter Escape by RNA Polymerase.- Promoter Function is Regulated at Two Distinct Phases of Transcription: Promoter Binding and RNA Chain Initiation.- The Biochemistry of the RNA Chain Initiation Phase of Transcription.- Parameters That Describe the RNA Chain Initiation Reaction at Different Promoters.- Factors That Affect the Initiation Reaction: Intrinsic Factors.- Factors That Affect the Initiation Reaction: Extrinsic Factors.- Models for the Mechanism of RNA Chain Initiation: Some Simple Models Do Not Account for What Is Known.- Models for the Mechanism of RNA Chain Initiation-Models Based on Recent Models for RNA Chain Elongation.- 3. Transcription Termination and Its Control.- Termination.- Antitermination.- 4. Codon Context, Translational Step-Times and Attenuation.- Overview.- Attenuation.- Codon Context and Translational Efficiency.- Effects of Codon Pair Bias on Translational Step-Times.- Discussion.- 5. Control by Antisense RNA.- Antisense RNAs Control Diverse Biological Functions.- Antisense RNAs Control Gene Expression at Many Different Post-Transcriptional Levels.- Antisense RNAs Pair to Their Target RNAs by Defined Mechanisms.- Overview.- 6. Translational Control of Gene Expression in E. Coli and Bacteriophage.- Translation Initiation.- Translational Operators.- Translational Repressors.- Mechanisms of Control.- Translational Control and mRNA Processing and/or Degradation.- The Role of Translational Control in Growth Rate Regulation.- Conclusions and Perspectives.- 7. Effects of DNA Supercoiling on Gene Expression.- Synopsis.- The Dependence of Transcription on the Cellular Level of DNA Gyrase and DNA Topoisomerase I.- Mechanistic Considerations.- Supercoiling of the DNA Template by Transcription.- Concluding Remarks.- 8. The HU and IHF Proteins: Accessory Factors for Complex Protein-DNA Assemblies.- Perspective.- Structure.- Interaction with Nucleic Acids.- Control of Intracellular Concentration and Activity.- Participation of IHF and HU in Well-Characterized Biochemical Processes.- Unfinished Business.- 9. The lac and gal Operons Today.- The lac and gal Operons Encode Enzymes of a Continuous Biochemical Pathway.- The Regulatory Circuits and Their Components.- Modulation of Promoters by cAMP*CRP.- Control of P2 by UTP in gal.- Natural Polarity.- Negative Control by Repressor-Operator Interactions.- Epilogue.- 10. The Maltose System.- and Scope.- The Positive Transcriptional Activator MalT.- The Maltose/Maltodextrin Transport System.- The Enzymes of the Maltose System.- Nonclassical Regulatory Phenomena.- Perspectives.- 11. The Phosphoenolpyruvate-Dependent Carbohydrate: Phosphotransferase System (PTS) and Control of Carbon Source Utilization.- Regulatory Phenomena Related to Carbon Source Utilization.- Bacterial Transport Systems and Global Regulatory Networks Form a Unit.- The Bacterial PTS Is a Transport and Signal Transduction System.- IIAGlc of the PTS Is Central to Carbon Catabolite Repression.- IIAGlc, the Regulation of Adenylate Cyclase Activity and of Intracellular cAMP Levels.- Not Only cAMP Levels, but Also CRP Levels Are Essential in Catabolite Repression.- IIAGlc and Inducer Exclusion.- Catabolite Repression and Inducer Exclusion Act in Concert.- Carbon Catabolite Repression through PTS-Control Is Part of a Stimulon.- Concluding Remarks.- 12. The Cap Modulon.- The Long History of CAP.- Cyclic AMP and Gene Expression.- CAP as a Global Regulator: The CAP Modulon.- CAP Binding at Target Promoters and Structural Studies.- Activation by CAP at "Simple"CRP.- Control of P2 by UTP in gal.- Natural Polarity.- Negative Control by Repressor-Operator Interactions.- Epilogue.- 10. The Maltose System.- and Scope.- The Positive Transcriptional Activator MalT.- The Maltose/Maltodextrin Transport System.- The Enzymes of the Maltose System.- Nonclassical Regulatory Phenomena.- Perspectives.- 11. The Phosphoenolpyruvate-Dependent Carbohydrate: Phosphotransferase System (PTS) and Control of Carbon Source Utilization.- Regulatory Phenomena Related to Carbon Source Utilization.- Bacterial Transport Systems and Global Regulatory Networks Form a Unit.- The Bacterial PTS Is a Transport and Signal Transduction System.- IIAGlc of the PTS Is Central to Carbon Catabolite Repression.- IIAGlc, the Regulation of Adenylate Cyclase Activity and of Intracellular cAMP Levels.- Not Only cAMP Levels, but Also CRP Levels Are Essential in Catabolite Repression.- IIAGlc and Inducer Exclusion.- Catabolite Repression and Inducer Exclusion Act in Concert.- Carbon Catabolite Repression through PTS-Control Is Part of a Stimulon.- Concluding Remarks.- 12. The Cap Modulon.- The Long History of CAP.- Cyclic AMP and Gene Expression.- CAP as a Global Regulator: The CAP Modulon.- CAP Binding at Target Promoters and Structural Studies.- Activation by CAP at "Simple" Promoters.- Activation by CAP at Complex Promoters.- CAP as a Repressor and a Co-Repressor.- CAP: Paradigm or Artifact?.- 13. Regulation of Nitrogen Assimilation.- The glnALG(glnA ntrBC) Operon.- The ?54-Dependent Promoter.- Transcriptional Enhancers.- Phosphorylation of NRI.- NRI/NRII as Two-Component Paradigm.- Activation of Transcription.- Response to Nitrogen Availability.- 14. History of the Pho System.- 15. Are the Multiple Signal Transduction Pathways of the Pho Regulon Due to Cross Talk or Cross Regulation?.- Genes for Pi Control of the Pho Regulon.- Transmembrane Signaling by Environmental Pi.- Genes for Pi Independent Controls of the Pho Regulon.- Activation by CreC and Acetyl Phosphate.- Cross Talk, Cross Regulation and a Hypothesis.- Is There Evidence for Cross Regulation?.- Overview and Prospects for Future Studies.- 16. The FNR Modulon and FNR-Regulated Gene Expression.- The Metabolic Arena.- The FNR Modulon.- The FNR Protein and Relationships with CAP.- The DNA-Binding Specificity of FNR.- In Vitro Transcription Activation and Repression.- Transcriptional Organization of Representative Promoters.- Potential FNR Contacts with RNA Polymerase and DNA-Bending.- The Mystery of Redox-Sensing.- Structural and Functional Homologs of FNR.- Concluding Remarks.- 17. The NAR Modulon Systems: Nitrate and Nitrite Regulation of Anaerobic Gene Expression.- Anaerobic Respiration.- The Characterization of the Nar Regulatory System.- Dual Two-Component Regulatory Systems.- The Role of Nitrite in the Nar Regulatory System.- The Sensor Proteins.- The Response Regulators.- Indirect Nitrate Regulation of Gene Expression.- Concluding Remarks.- 18. Regulation of Aerobic and Anaerobic Metabolism by the Arc System.- Identification of the arc Genes.- In Vivo Studies of arc Mutants.- In Vitro Phosphorylation Studies.- The Arc Modulon.- ArcA DNA Binding.- The Arc Stimulus.- Future Studies.- 19. The Porin Regulon: A Paradigm for the Two-Component Regulatory Systems.- Background.- The History of Porin Regulation.- The Structure of the ompB Locus.- The Structure of the ompF and ompC Genes.- The Roles of OmpR and EnvZ.- Phosphorylation and Signal Transduction.- Summary and Conclusions.- 20. The Leucine\Lrp Regulon.- The Leucine-Responsive Regulatory Protein.- Regulation of Lrp Synthesis.- Target Operons of Lrp and Mutant Phenotypes.- Lrp as a Chromosome Organizer.- Molecular Aspects of Lrp Interactions at Individual Promoters.- 21. Adaptive responses to Oxidative Stress: The soxRS and oxyR Regulons.- Reactive Oxygen Species.- Antioxidant Defenses.- Oxidative Stress.- Global Responses to Oxidative Stress.- The soxRS Regulon.- The oxyR Regulon.- Control of Antibiotic Resistance Genes.- 22. The SOS Regulatory System.- and Current Regulatory Model.- Development of the SOS Model.- Recent Developments.- Behavior of the SOS Gene Regulatory Circuitry.- Future Prospects.- 23. Heat Shock Regulation.- Properties of Important Heat Shock Proteins.- Regulation of the ?32-Promoted Heat Shock Response.- A Second Heat Shock Regulon.- The ?54-Promoted Stress Response.- Heat Shock or Stress Responses in Other Eubacteria.- 24. Roles for Energy-Dependent Proteases in Regulatory Cascades.- The Proteases and Their Targets.- Summary and General Conclusions.- 25. Control of rRNA and Ribosome Synthesis.- rRNA Gene Organization.- High Activity of rRNA Synthesis Rates.- Stringent Control.- Growth Rate Dependent Control.- Additional Considerations.- Conclusion and Future Prospects.- 26. Cell Division.- The Cell Division Process.- Essential Cell Division Genes.- Transcriptional Regulation of Cell Division Genes.- Translational Control.- Division Inhibitors.- Cell Division Inhibition by Mutations in Genes That Do Not Code for Cell Division Proteins.- Past, Present and Future.- 27. Regulation of Gene Expression in Stationary Phase.- The ?s Regulon.- RpoS Regulation.

Regulation of Gene Expression in Escherichia Coli

https://mmbr.asm.org/content/mmbr/60/1/21.full.pdf

D.L. Roberts

Papers

Signal transduction by the EnvZ-OmpR phosphotransfer system in bacteria.

Identification of the site of phosphorylation on the osmosensor, EnvZ, of Escherichia coli.