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The history of Shigella, the causative agent of bacillary dysentery, is a long and fascinating one. This brief historical account starts with descriptions of the disease and its impact on human health from ancient time to the present. Our story of the bacterium starts just before the identification of the dysentery bacillus by Kiyoshi Shiga in 1898 and follows the scientific discoveries and principal scientists who contributed to the elucidation of Shigella pathogenesis in the first 100 years. Over the past century, Shigella has proved to be an outstanding model of an invasive bacterial pathogen and has served as a paradigm for the study of other bacterial pathogens. In addition to invasion of epithelial cells, some of those shared virulence traits include toxin production, multiple-antibiotic resistance, virulence genes encoded on plasmids and bacteriophages, global regulation of virulence genes, pathogenicity islands, intracellular motility, remodeling of host cytoskeleton, inflammation/polymorphonuclear leukocyte signaling, apoptosis induction/inhibition, and "black holes" and antivirulence genes. While there is still much to learn from studying Shigella pathogenesis, what we have learned so far has also contributed greatly to our broader understanding of bacterial pathogenesis.

In Escherichia coli, proteins found in the periplasm or the outer membrane are exported from the cytoplasm by the general secretory, Sec, system before they acquire stably folded structure. This dynamic process involves intricate interactions among cytoplasmic and membrane proteins, both peripheral and integral, as well as lipids. In vivo, both ATP hydrolysis and proton motive force are required. Here, we review the Sec system from the inception of the field through early 2016, including biochemical, genetic, and structural data.

Among all the systems developed by enterobacteria to face osmotic stress, only osmoregulated periplasmic glucans (OPGs) were found to be modulated during osmotic fluxes. First detected in 1973 by E.P. Kennedy's group in a study of phospholipid turnover in Escherichia coli, OPGs have been shown across alpha, beta, and gamma subdivisions of the proteobacteria. Discovery of OPG-like compounds in the epsilon subdivision strongly suggested that the presence of periplasmic glucans is essential for almost all proteobacteria. This article offers an overview of the different classes of OPGs. Then, the biosynthesis of OPGs and their regulation in E. coli and other species are discussed. Finally, the biological role of OPGs is developed. Beyond structural function, OPGs are involved in pathogenicity, in particular, by playing a role in signal transduction pathways. Recently, OPG synthesis proteins have been suggested to control cell division and growth rate.

σ^N (also σ⁵⁴) is an alternative sigma factor subunit of the RNA polymerase complex that regulates the expression of genes from many different ontological groups. It is broadly conserved in the Eubacteria with major roles in nitrogen metabolism, membrane biogenesis, and motility. σ^N is encoded as the first gene of a five-gene operon including rpoN (σ^N), ptsN, hpf, rapZ, and npr that has been genetically retained among species of Escherichia, Shigella, and Salmonella. In an increasing number of bacteria, σ^N has been implicated in the control of genes essential to pathogenic behavior, including those involved in adherence, secretion, immune subversion, biofilm formation, toxin production, and resistance to both antimicrobials and biological stressors. For most pathogens how this is achieved is unknown. In enterohemorrhagic Escherichia coli (EHEC) O157, Salmonella enterica, and Borrelia burgdorferi, regulation of virulence by σ^N requires another alternative sigma factor, σ^S, yet the model by which σ^N-σ^S virulence regulation is predicted to occur is varied in each of these pathogens. In this review, the importance of σ^N to bacterial pathogenesis is introduced, and common features of σ^N-dependent virulence regulation discussed. Emphasis is placed on the molecular mechanisms underlying σ^N virulence regulation in E. coli O157. This includes a review of the structure and function of regulatory pathways connecting σ^N to virulence expression, predicted input signals for pathway stimulation, and the role for cognate σ^N activators in initiation of gene systems determining pathogenic behavior.

Escherichia coli K-12 and Salmonella enterica serovar Typhimurium LT2 became standard organisms for genetic analysis during the Truman administration. Half a century later, genetic analysis with these strains had become an art form, interpreted through 23 articles in the ambitious two-volume masterpiece edited by the late Fred Neidhardt and colleagues. These legacy articles now are available through EcoSal Plus, so as to inform and inspire contemporary genetic analyses in these standard organisms and their relatives.

The insertion and assembly of proteins into the inner membrane of bacteria are crucial for many cellular processes, including cellular respiration, signal transduction, and ion and pH homeostasis. This process requires efficient membrane targeting and insertion of proteins into the lipid bilayer in their correct orientation and proper conformation. Playing center stage in these events are the targeting components, signal recognition particle (SRP) and the SRP receptor FtsY, as well as the insertion components, the Sec translocon and the YidC insertase. Here, we will discuss new insights provided from the recent high-resolution structures of these proteins. In addition, we will review the mechanism by which a variety of proteins with different topologies are inserted into the inner membrane of Gram-negative bacteria. Finally, we report on the energetics of this process and provide information on how membrane insertion occurs in Gram-positive bacteria and Archaea. It should be noted that most of what we know about membrane protein assembly in bacteria is based on studies conducted in Escherichia coli.

Systems metabolic engineering, which recently emerged as metabolic engineering integrated with systems biology, synthetic biology, and evolutionary engineering, allows engineering of microorganisms on a systemic level for the production of valuable chemicals far beyond its native capabilities. Here, we review the strategies for systems metabolic engineering and particularly its applications in Escherichia coli. First, we cover the various tools developed for genetic manipulation in E. coli to increase the production titers of desired chemicals. Next, we detail the strategies for systems metabolic engineering in E. coli, covering the engineering of the native metabolism, the expansion of metabolism with synthetic pathways, and the process engineering aspects undertaken to achieve higher production titers of desired chemicals. Finally, we examine a couple of notable products as case studies produced in E. coli strains developed by systems metabolic engineering. The large portfolio of chemical products successfully produced by engineered E. coli listed here demonstrates the sheer capacity of what can be envisioned and achieved with respect to microbial production of chemicals. Systems metabolic engineering is no longer in its infancy; it is now widely employed and is also positioned to further embrace next-generation interdisciplinary principles and innovation for its upgrade. Systems metabolic engineering will play increasingly important roles in developing industrial strains including E. coli that are capable of efficiently producing natural and nonnatural chemicals and materials from renewable nonfood biomass.

A very large type I polypeptide begins to reel out from a ribosome; minutes later, the still unidentifiable polypeptide, largely lacking secondary structure, is now in some cases a thousand or more residues longer. Synthesis of the final hundred C-terminal residues commences. This includes the identity code, the secretion signal within the last 50 amino acids, designed to dock with a waiting ATP binding cassette (ABC) transporter. What happens next is the subject of this review, with the main, but not the only focus on hemolysin HlyA, an RTX protein toxin secreted by the type I system. Transport substrates range from small peptides to giant proteins produced by many pathogens. These molecules, without detectable cellular chaperones, overcome enormous barriers, crossing two membranes before final folding on the cell surface, involving a unique autocatalytic process.Unfolded HlyA is extruded posttranslationally, C-terminal first. The transenvelope "tunnel" is formed by HlyB (ABC transporter), HlyD (membrane fusion protein) straddling the inner membrane and periplasm and TolC (outer membrane). We present a new evaluation of the C-terminal secretion code, and the structure function of HlyD and HlyB at the heart of this nanomachine. Surprisingly, key details of the secretion mechanism are remarkably variable in the many type I secretion system subtypes. These include alternative folding processes, an apparently distinctive secretion code for each type I subfamily, and alternative forms of the ABC transporter; most remarkably, the ABC protein probably transports peptides or polypeptides by quite different mechanisms. Finally, we suggest a putative structure for the Hly-translocon, HlyB, the multijointed HlyD, and the TolC exit.

Salmonellosis, caused by members of the genus Salmonella, is responsible for considerable global morbidity and mortality in both animals and humans. In this review, we will discuss the pathogenesis of Salmonella enterica serovar Typhi and Salmonella enterica serovar Typhimurium, focusing on human Salmonella infections. We will trace the path of Salmonella through the body, including host entry sites, tissues and organs affected, and mechanisms involved in both pathogenesis and stimulation of host immunity. Careful consideration of the natural progression of disease provides an important context in which attenuated live oral vaccines can be rationally designed and developed. With this in mind, we will describe a series of attenuated live oral vaccines that have been successfully tested in clinical trials and demonstrated to be both safe and highly immunogenic. The attenuation strategies summarized in this review offer important insights into further development of attenuated vaccines against other Salmonella for which live oral candidates are currently unavailable.