Environmental Regulation Of Virulence Gene Expression In Staphylococcus Aureus

A comprehensive compendium of scholarly contributions relating to bacterial virulence gene regulation. • Provides insights into global control and the switch between distinct infectious states (e.g., acute vs. chronic). • Considers key issues about the mechanisms of gene regulation relating to: surface factors, exported toxins and export mechanisms. • Reflects on how the regulation of intracellular lifestyles and the response to stress can ultimately have an impact on the outcome of an infection. • Highlights and examines some emerging regulatory mechanisms of special significance. • Serves as an ideal compendium of valuable topics for students, researchers and faculty with interests in how the mechanisms of gene regulation ultimately affect the outcome of an array of bacterial infectious diseases.

Bacteria in various habitats are subject to continuously changing environmental conditions, such as nutrient deprivation, heat and cold stress, UV radiation, oxidative stress, dessication, acid stress, nitrosative stress, cell envelope stress, heavy metal exposure, osmotic stress, and others. In order to survive, they have to respond to these conditions by adapting their physiology through sometimes drastic changes in gene expression. In addition they may adapt by changing their morphology, forming biofilms, fruiting bodies or spores, filaments, Viable But Not Culturable (VBNC) cells or moving away from stress compounds via chemotaxis. Changes in gene expression constitute the main component of the bacterial response to stress and environmental changes, and involve a myriad of different mechanisms, including (alternative) sigma factors, bi- or tri-component regulatory systems, small non-coding RNA’s, chaperones, CHRIS-Cas systems, DNA repair, toxin-antitoxin systems, the stringent response, efflux pumps, alarmones, and modulation of the cell envelope or membranes, to name a few. Many regulatory elements are conserved in different bacteria; however there are endless variations on the theme and novel elements of gene regulation in bacteria inhabiting particular environments are constantly being discovered. Especially in (pathogenic) bacteria colonizing the human body a plethora of bacterial responses to innate stresses such as pH, reactive nitrogen and oxygen species and antibiotic stress are being described. An attempt is made to not only cover model systems but give a broad overview of the stress-responsive regulatory systems in a variety of bacteria, including medically important bacteria, where elucidation of certain aspects of these systems could lead to treatment strategies of the pathogens. Many of the regulatory systems being uncovered are specific, but there is also considerable “cross-talk” between different circuits. Stress and Environmental Regulation of Gene Expression and Adaptation in Bacteria is a comprehensive two-volume work bringing together both review and original research articles on key topics in stress and environmental control of gene expression in bacteria. Volume One contains key overview chapters, as well as content on one/two/three component regulatory systems and stress responses, sigma factors and stress responses, small non-coding RNAs and stress responses, toxin-antitoxin systems and stress responses, stringent response to stress, responses to UV irradiation, SOS and double stranded systems repair systems and stress, adaptation to both oxidative and osmotic stress, and desiccation tolerance and drought stress. Volume Two covers heat shock responses, chaperonins and stress, cold shock responses, adaptation to acid stress, nitrosative stress, and envelope stress, as well as iron homeostasis, metal resistance, quorum sensing, chemotaxis and biofilm formation, and viable but not culturable (VBNC) cells. Covering the full breadth of current stress and environmental control of gene expression studies and expanding it towards future advances in the field, these two volumes are a one-stop reference for (non) medical molecular geneticists interested in gene regulation under stress.

Many pathogenic bacteria are dependent on their ability to swiftly sense the surrounding environment and thus coordinate the production of virulence factors to facilitate their pathogenesis. The success of human pathogen Staphylococcus aureus in pathogenesis is largely attributed to the sophisticated signaling and regulatory network consisting of 1) sixteen two-component systems (TCSs) and 2) multiple global transcriptional regulators. As a paradigm of bacterial signal transduction, bacterial two-component systems typically fulfill signaling processes through His/Asp phospho-relay between the sensor kinase and the response regulator. However, for a particular TCS in S. aureus, the molecular signal responsible for its activation/deactivation is largely unknown. To this end, in this thesis, Chapter One, Chapter Two, Chapter Three, and Chapter Four focus on elucidating or reinvestigating molecular signals or mechanisms of three TCSs (AirSR, quorum-sensing Agr, and SaeRS) that are shown to be critical for staphylococcal infectivity according to the mouse model of infection. In addition to TCS-mediated signaling events, the role of eukaryotic-like Ser/Thr phosphorylation in bacterial signaling has received ample attention in recent years. Several studies suggested that this type of phosphorylation, mainly mediated by the sole eukaryotic-like Ser/Thr phosphatase-kinase pair (Stp1-Stk1) in S. aureus, could occur to several global transcriptional regulators (MgrA and SarA) and is important for S. aureus virulence regulation. Instead, our study presented in Chapter Five demonstrates that another type protein modification mediated by Stp1-Stk1, Cys-phosphorylation, occurs at the sole Cys residue conserved in global transcriptional regulators such as MgrA, SarA, and SarZ, and that this modification impairs the DNA-binding ability of these proteins, thus modulating the target virulence gene expression. Chapter Five further indicates that Cys-phosphorylation is a widespread but overlooked posttranslational modification at least in S. aureus, of which the biological significance has yet to be illustrated. As proof of principle, Chapter Six describes a small-molecule approach that diminishes staphylococcal virulence by blocking the DNA binding of the transcriptional regulator MgrA, demonstrating that virulence regulation is a druggable target for future antibiotic development.

This book illustrates the importance and significance of Quorum sensing (QS), it’s critical roles in regulating diverse cellular functions in microbes, including bioluminescence, virulence, pathogenesis, gene expression, biofilm formation and antibiotic resistance. Microbes can coordinate population behavior with small molecules called autoinducers (AHL) which serves as a signal of cellular population density, triggering new patterns of gene expression for mounting virulence and pathogenesis. Therefore, these microbes have the competence to coordinate and regulate explicit sets of genes by sensing and communicating amongst themselves utilizing variety of signals. This book descry emphasizes on how bacteria can coordinate an activity and synchronize their response to external signals and regulate gene expression. The chapters of the book provide the recent advancements on various functional aspects of QS systems in different gram positive and gram negative organisms. Finally, the book also elucidates a comprehensive yet a representative description of a large number of challenges associated with quorum sensing signal molecules viz. virulence, pathogenesis, antibiotic synthesis, biosurfactants production, persister cells, cell signaling and biofilms, intra and inter-species communications, host-pathogen interactions, social interactions & swarming migration in biofilms.

Microbial relationships with all life forms can be as free living, symbiotic or pathogenic. Human beings harbor 10 times more microbial cells than their own. Bacteria are found on the skin surface, in the gut and other body parts. Bacteria causing diseases are the most worrisome. Most of the infectious diseases are caused by bacterial pathogens with an ability to form biofilm. Bacteria within the biofilm are up to 1000 times more resistant to antibiotics. This has taken a more serious turn with the evolution of multiple drug resistant bacteria. Health Departments are making efforts to reduce high mortality and morbidity in man caused by them. Bacterial Quorum sensing (QS), a cell density dependent phenomenon is responsible for a wide range of expressions such as pathogenesis, biofilm formation, competence, sporulation, nitrogen fixation, etc. Majority of these organisms that are important for medical, agriculture, aquaculture, water treatment and remediation, archaeological departments are: Aeromonas, Acinetobacter, Bacillus, Clostridia, Enterococcus, Pseudomonas, Vibrio and Yersinia spp. Biosensors and models have been developed to detect QS systems. Strategies for inhibiting QS system through natural and synthetic compounds have been presented here. The biotechnological applications of QS inhibitors (QSIs) in diverse areas have also been dealt with. Although QSIs do not affect growth and are less likely to impose selective pressure on bacteria, however, a few reports have raised doubts on the fate of QSIs. This book addresses a few questions. Will bacteria develop mechanisms to evade QSIs? Are we watching yet another defeat at the hands of bacteria? Or will we be acting intelligently and survive the onslaughts of this Never Ending battle?

Molecular Basis of Bacterial Pathogenesis focuses on the molecular mechanism of disease associated with bacterial pathogens. Topics covered include the population genetics of bacterial pathogenesis; environmental modulation of gene expression in gram-negative pathogens; and bacterial invasion and intracellular growth. Bacterial toxins are also discussed. This volume is comprised of 20 chapters and begins with an overview of pathogenesis, paying particular attention to common elements and genetic mechanisms of regulation. The discovery that many bacterial pathogens are clonal, with individual clones often having a greater virulence than others, is then considered. The next section deals with the regulation of synthesis of surface components and their role in colonization of the host and/or evasion of the host immune defense systems; antigenic variation and its role in evasion of the host immune response; and the role of iron acquisition systems in the colonization of the host. Subsequent chapters explore the invasion and intracellular growth of facultative and obligate intracellular parasites. The last section is devoted to studies on the role of bacterial toxic products in pathogenesis. Bacterial lipopolysaccharides (endotoxins) and exotoxins are described. This book should be of interest to molecular biologists, physiologists, clinical specialists, pathologists, and geneticists.

Staphylococci remain the most important cause of hospital-acquiredinfections in the U.S. and MRSA has become the most common cause ofskin and soft tissue infection in many parts of the world. There is now a much greater understanding of the physiology andevolution of the staphylococci and this new edition reflects therapid advancements in knowledge about this pathogen and provides acomprehensive review from both clinical and basic scienceperspectives. The first section addresses the basic biology of thestaphylococci, their molecular genetics, host defenses and hostevasion, virulence determinants, mechanisms of antibioticresistance, and laboratory techniques. The second section dealswith epidemiology, and the third section provides an overview ofthe varied clinical manifestations of human staphylococcalinfections. The fourth section covers prevention and treatment ofthese often life-threatening infections. Written by experts from around the globe, this book is essentialreading for all clinicians and basic scientists studying thestaphylococci.