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Annual Review of Microbiology - Volume 65, 2011
Volume 65, 2011
- Preface
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To the Happy Few
Vol. 65 (2011), pp. 1–18More LessI became a microbiologist in post-WWII Japan, working with Toshio Fukasawa on galactose metabolism in Salmonella. We characterized mutants defective in UDP-galactose 4-epimerase, which produced a defective lipopolysaccharide, and this opened doors for me to study lipopolysaccharide biosynthesis, which I pursued in the United States, in the laboratory of Herman Kalckar. After I moved to Berkeley, California, in 1969, I became interested in the function of bacterial outer membranes, a line of work that led to the discovery and characterization of porins as well as the studies on the mycobacterial cell wall. In the early 1990s, it became clear that the outer membrane permeability barrier and the activity of periplasmic β-lactamase are not enough to explain the resistance of some strains to β-lactam antibiotics, and the search for the missing factor led to the discovery of RND family multidrug efflux pumps, subjects that continue to fascinate me to this day.
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Regulation of DnaA Assembly and Activity: Taking Directions from the Genome
Vol. 65 (2011), pp. 19–35More LessTo ensure proper timing of chromosome duplication during the cell cycle, bacteria must carefully regulate the activity of initiator protein DnaA and its interactions with the unique replication origin oriC. Although several protein regulators of DnaA are known, recent evidence suggests that DnaA recognition sites, in multiple genomic locations, also play an important role in controlling assembly of pre-replicative complexes. In oriC, closely spaced high- and low-affinity recognition sites direct DnaA-DnaA interactions and couple complex assembly to the availability of active DnaA-ATP. Additional recognition sites at loci distant from oriC modulate DnaA-ATP availability by repressing new synthesis, recharging inactive DnaA-ADP, or titrating DnaA. Relying on genomic DnaA binding sites, as well as protein regulators, to control DnaA function appears to provide the best combination of high precision and dynamic regulation necessary to couple DNA replication with cell growth over a range of nutritional conditions.
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Regulation of Alternative Sigma Factor Use
Vol. 65 (2011), pp. 37–55More LessAlternative bacterial sigma factors bind the catalytic core RNA polymerase to confer promoter selectivity on the holoenzyme. The different holoenzymes are thus programmed to recognize the distinct promoter classes in the genome to allow coordinated activation of discrete sets of genes needed for adaptive responses. To form the holoenzymes, the different sigma factors must be available to compete for their common substrate (core RNA polymerase). This review highlights (a) the roles of antisigma factors in controlling the availability of alternative sigma factors and (b) the involvement of diverse regulatory molecules that promote the use of alternative sigma factors through subversion of the domineering housekeeping σ70. The latter include the nucleotide alarmone ppGpp and small proteins (DksA, Rsd, and Crl), which directly target the transcriptional machinery to mediate their effects.
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Fungal Protein Production: Design and Production of Chimeric Proteins
Vol. 65 (2011), pp. 57–69More LessFor more than a century, filamentous fungi have been used for the production of a wide variety of endogenous enzymes of industrial interest. More recently, with the use of genetic engineering tools developed for these organisms, this use has expanded for the production of nonnative heterologous proteins. In this review, an overview is given of examples describing the production of a special class of these proteins, namely chimeric proteins. The production of two types of chimeric proteins have been explored: (a) proteins grafted for a specific substrate-binding domain and (b) fusion proteins containing two separate enzymatic activities. Various application areas for the use of these chimeric proteins are described.
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Structure and Function of MARTX Toxins and Other Large Repetitive RTX Proteins
Vol. 65 (2011), pp. 71–90More LessThe Repeats-in-Toxins (RTX) family of proteins classically consists of cytolysins and hemolysins. Over the past decade, genome sequencing revealed the existence of very large members of this family. These are all repetitive proteins ranging in size from 200 to 900 kDa that function as toxins or adhesins. Many are exported by Type I secretion. One major new subfamily is the large repetitive RTX adhesins and biofilm-associated proteins. These are characterized by 80- to 300-amino-acid repeats ordered in tandem, although the sequence and number of the repeats vary by protein. The second major new subfamily is the multifunctional-autoprocessing RTX toxins, which are associated with cytotoxicity and pathogenesis. These proteins are in turn distantly related to Yersinia hypothetical RTX proteins that may autoprocess by a similar mechanism. This review discusses current knowledge regarding the structure and function of these new subfamilies of RTX proteins.
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Eukaryotic Picoplankton in Surface Oceans
Vol. 65 (2011), pp. 91–110More LessThe eukaryotic picoplankton is a heterogeneous collection of small protists 1 to 3 μm in size populating surface oceans at abundances of 102 to 104 cells ml−1. Pigmented cells are important primary producers that are at the base of food webs. Colorless cells are mostly bacterivores and play key roles in channeling bacteria to higher trophic levels as well as in nutrient recycling. Mixotrophy and parasitism are relevant but less investigated trophic paths. Molecular surveys of picoeukaryotes have unveiled a large phylogenetic diversity and new lineages, and it is critical to understand the ecological and evolutionary significance of this large and novel diversity. A main goal is to assess how individuals are organized in taxonomic units and how they participate in ecological processes. Picoeukaryotes are convincingly integral members of marine ecosystems in terms of cell abundance, biomass, activity, and diversity and they play crucial roles in food webs and biogeochemical cycles.
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Life on the Outside: The Rescue of Coxiella burnetii from Its Host Cell*
Vol. 65 (2011), pp. 111–128More LessFor over seven decades, Coxiella burnetii, the causative agent of human Q fever, has been considered a prototypical obligate intracellular bacterium that relies exclusively on a eukaryotic cell for growth. Intracellularly, the organism prospers in an acidified, phagolysosome-like vacuole. C. burnetii has evolved to replicate in this harsh compartment by a mechanism involving acid activation of metabolism. The ∼2 Mb genome of C. burnetii is about twice the size of genomes of most obligate intracellular bacteria, and the organism's central metabolic pathways are largely intact. The absence of extensive genome reduction suggests the adaptation of C. burnetii to an obligate intracellular lifestyle is a recent evolutionary event. Indeed, insight from early work on C. burnetii metabolism, along with new information gained from metabolic pathway reconstructions, nutrient typing, and expression profiling, allowed the rescue of C. burnetii from its host cell to regain the axenic growth capacity of its ancestors. This advance removes the extensive experimental obstacles associated with intracellular obligatism and opens the door for a renaissance in C. burnetii research.
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Molecular Mechanisms of Staphylococcus aureus Iron Acquisition
Vol. 65 (2011), pp. 129–147More LessThe unique redox potential of iron makes it an ideal cofactor in diverse biochemical reactions. Iron is therefore vital for the growth and proliferation of nearly all organisms, including pathogenic bacteria. Vertebrates sequester excess iron within proteins in order to alleviate toxicity and restrict the amount of free iron available for invading pathogens. Restricting the growth of infectious microorganisms by sequestering essential nutrients is referred to as nutritional immunity. In order to circumvent nutritional immunity, bacterial pathogens have evolved elegant systems that allow for the acquisition of iron during infection. The gram-positive extracellular pathogen Staphylococcus aureus is a commensal organism that can cause severe disease when it gains access to underlying tissues. Iron acquisition is required for S. aureus colonization and subsequent pathogenesis. Herein we review the strategies S. aureus employs to obtain iron through the production of siderophores and the consumption of host heme.
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Protein Quality Control in the Bacterial Periplasm
Vol. 65 (2011), pp. 149–168More LessProtein quality control involves sensing and treatment of defective or incomplete protein structures. Misfolded or mislocalized proteins trigger dedicated signal transduction cascades that upregulate the production of protein quality-control factors. Corresponding proteases and chaperones either degrade or repair damaged proteins, thereby reducing the level of aggregation-prone molecules. Because the periplasm of gram-negative bacteria is particularly exposed to environmental changes and respective protein-folding stresses connected with the presence of detergents, low or high osmolarity of the medium, elevated temperatures, and the host's immune response, fine-tuned protein quality control systems are essential for survival under these unfavorable conditions. This review discusses recent advances in the identification and characterization of the key cellular factors and the emerging general principles of the underlying molecular mechanisms.
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Prospects for the Future Using Genomics and Proteomics in Clinical Microbiology
Vol. 65 (2011), pp. 169–188More LessThe availability of genome sequences has revolutionized the fields of microbiology and infectious diseases. Indeed, more than 1,000 bacterial genomes and 3,000 viral genomes, including representatives of all significant human pathogens, have been sequenced to date. Owing to this tremendous amount of data, genomes are regarded as chimeras of sequence fragments from various origins. Coupled with novel proteomic analyses, genome sequencing has also resulted in unprecedented advances in pathogen diagnosis and genotyping and in the detection of virulence and antibiotic resistance. Herein, we review current achievements of genomics and proteomics and discuss potential developments for clinical microbiology laboratories.
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The RpoS-Mediated General Stress Response in Escherichia coli*
Vol. 65 (2011), pp. 189–213More LessUnder conditions of nutrient deprivation or stress, or as cells enter stationary phase, Escherichia coli and related bacteria increase the accumulation of RpoS, a specialized sigma factor. RpoS-dependent gene expression leads to general stress resistance of cells. During rapid growth, RpoS translation is inhibited and any RpoS protein that is synthesized is rapidly degraded. The complex transition from exponential growth to stationary phase has been partially dissected by analyzing the induction of RpoS after specific stress treatments. Different stress conditions lead to induction of specific sRNAs that stimulate RpoS translation or to induction of small-protein antiadaptors that stabilize the protein. Recent progress has led to a better, but still far from complete, understanding of how stresses lead to RpoS induction and what RpoS-dependent genes help the cell deal with the stress.
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Bacterial Osmoregulation: A Paradigm for the Study of Cellular Homeostasis
Vol. 65 (2011), pp. 215–238More LessTo thrive, cells must control their own physical and chemical properties. This process is known as cellular homeostasis. The dilute solutions traditionally favored by experimenters do not simulate the cytoplasm, where macromolecular crowding and preferential interactions among constituents may dominate critical processes. Solutions that do simulate cytoplasmic conditions are now being characterized. Corresponding cytoplasmic properties can be varied systematically by imposing osmotic stress. This osmotic stress approach is revealing how cytoplasmic properties modulate protein folding and protein–nucleic acid interactions. Results suggest that cytoplasmic homeostasis may require adjustments to multiple, interwoven cytoplasmic properties. Osmosensory transporters with diverse structures and bioenergetic mechanisms activate in response to osmotic stress as other proteins inactivate. These transporters are serving as paradigms for the study of in vivo protein-solvent interactions. Experimenters have proposed three different osmosensory mechanisms. Distinct mechanisms may exist, or these proposals may reflect different perceptions of a single, unifying mechanism.
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Lipoprotein Sorting in Bacteria
Vol. 65 (2011), pp. 239–259More LessBacterial lipoproteins are synthesized as precursors in the cytoplasm and processed into mature forms on the cytoplasmic membrane. A lipid moiety attached to the N terminus anchors these proteins to the membrane surface. Many bacteria are predicted to express more than 100 lipoproteins, which play diverse functions on the cell surface. The Lol system, composed of five proteins, catalyzes the localization of Escherichia coli lipoproteins to the outer membrane. Some lipoproteins play vital roles in the sorting of other lipoproteins, lipopolysaccharides, and β-barrel proteins to the outer membrane. On the basis of results from biochemical, genetic, and structural studies, we discuss the biogenesis of lipoproteins in bacteria, their importance in cellular functions, and the molecular mechanisms underlying efficient sorting of hydrophobic lipoproteins to the outer membrane through the hydrophilic periplasm.
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Ligand-Binding PAS Domains in a Genomic, Cellular, and Structural Context
Vol. 65 (2011), pp. 261–286More LessPer-Arnt-Sim (PAS) domains occur in proteins from all kingdoms of life. In the bacterial kingdom, PAS domains are commonly positioned at the amino terminus of signaling proteins such as sensor histidine kinases, cyclic-di-GMP synthases/hydrolases, and methyl-accepting chemotaxis proteins. Although these domains are highly divergent at the primary sequence level, the structures of dozens of PAS domains across a broad section of sequence space have been solved, revealing a conserved three-dimensional architecture. An all-versus-all alignment of 63 PAS structures demonstrates that the PAS domain family forms structural clades on the basis of two principal variables: (a) topological location inside or outside the plasma membrane and (b) the class of small molecule that they bind. The binding of a chemically diverse range of small-molecule metabolites is a hallmark of the PAS domain family. PAS ligand binding either functions as a primary cue to initiate a cellular signaling response or provides the domain with the capacity to respond to secondary physical or chemical signals such as gas molecules, redox potential, or photons. This review synthesizes the current state of knowledge of the structural foundations and evolution of ligand recognition and binding by PAS domains.
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How Viruses and Toxins Disassemble to Enter Host Cells
Vol. 65 (2011), pp. 287–305More LessMany viruses and toxins disassemble to enter host cells and cause disease. These conformational changes must be orchestrated temporally and spatially during entry to avoid premature disassembly leading to nonproductive pathways. Although viruses and toxins are evolutionarily distinct toxic agents, emerging findings in their respective fields have revealed that the cellular locations supporting disassembly, the host factors co-opted during disassembly, the nature of the conformational changes, and the physiological function served by disassembly are strikingly conserved. Here, we examine some of the shared disassembly principles observed in model viruses and toxins. Where appropriate, we also underscore their differences. Our major intention is to draw together the fields of viral and toxin cell entry by using lessons gleaned from each field to inform and benefit one another.
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Turning Hepatitis C into a Real Virus
Vol. 65 (2011), pp. 307–327More LessThe reality of hepatitis C is inescapable for the estimated 130 million people worldwide chronically infected with the virus. Yet this pathogen has been notoriously difficult to move from the infected individual into experimental systems, and each advance—from the identification of the infectious agent to its culture and study—has been a significant challenge. As a result of unrelenting technical hurdles, preventative and therapeutic options have been slow to reach hepatitis C patients. More than 35 years since the recognition of the disease, there is no vaccine available, and the only approved treatment, a combination of pegylated interferon-alpha (IFN-α) and ribavirin, is frequently ineffective. Decades of research, however, have resulted in systematic progress and much is now known about this once elusive pathogen. Most importantly, key breakthroughs have stimulated drug discovery, and the first generation of specifically targeted antiviral inhibitors is poised to enter the market. This review provides a look back at progress in developing tractable model systems for this important agent of chronic hepatitis.
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Recombination and DNA Repair in Helicobacter pylori
Vol. 65 (2011), pp. 329–348More LessAll organisms have pathways that repair the genome, ensuring their survival and that of their progeny. But these pathways also serve to diversify the genome, causing changes at the nucleotide, whole gene, and genome structure levels. Sequencing of bacteria has revealed wide allelic diversity and differences in gene content within the same species, highlighting the importance of understanding pathways of recombination and DNA repair. The human stomach pathogen Helicobacter pylori is an excellent model system for studying these pathways. H. pylori harbors major recombination and repair pathways and is naturally competent, facilitating its ability to diversify its genome. Elucidation of DNA recombination, repair, and diversification programs in this pathogen will reveal connections between these pathways and their importance to infection.
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Kin Discrimination and Cooperation in Microbes
Vol. 65 (2011), pp. 349–367More LessRecognition of relatives is important in microbes because they perform many behaviors that have costs to the actor while benefiting neighbors. Microbes cooperate for nourishment, movement, virulence, iron acquisition, protection, quorum sensing, and production of multicellular biofilms or fruiting bodies. Helping others is evolutionarily favored if it benefits others who share genes for helping, as specified by kin selection theory. If microbes generally find themselves in clonal patches, then no special means of discrimination is necessary. Much real discrimination is actually of kinds, not kin, as in poison-antidote systems, such as bacteriocins, in which cells benefit their own kind by poisoning others, and in adhesion systems, in which cells of the same kind bind together. These behaviors can elevate kinship generally and make cooperation easier to evolve and maintain.
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Dinoflagellate Genome Evolution
Vol. 65 (2011), pp. 369–387More LessThe dinoflagellates are an ecologically important group of microbial eukaryotes that have evolved many novel genomic characteristics. They possess some of the largest nuclear genomes among eukaryotes arranged on permanently condensed liquid-crystalline chromosomes. Recent advances have revealed the presence of genes arranged in tandem arrays, trans-splicing of messenger RNAs, and a reduced role for transcriptional regulation compared to other eukaryotes. In contrast, the mitochondrial and plastid genomes have the smallest gene content among functional eukaryotic organelles. Dinoflagellate biology and genome evolution have been dramatically influenced by lateral transfer of individual genes and large-scale transfer of genes through endosymbiosis. Next-generation sequencing technologies have only recently made genome-scale analyses of these organisms possible, and these new methods are helping researchers better understand the biology and evolution of this enigmatic group of eukaryotes.
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Motility and Chemotaxis in Campylobacter and Helicobacter
Vol. 65 (2011), pp. 389–410More LessFlagellar motility of Campylobacter jejuni and Helicobacter pylori influences host colonization by promoting migration through viscous milieus such as gastrointestinal mucus. This review explores mechanisms C. jejuni and H. pylori employ to control flagellar biosynthesis and chemotactic responses. These microbes tightly control the activities of σ54 and σ28 to mediate ordered flagellar gene expression. In addition to phase-variable and posttranslational mechanisms, flagellar biosynthesis is regulated spatially and numerically so that only a certain number of organelles are placed at polar sites. To mediate chemotaxis, C. jejuni and H. pylori combine basic chemotaxis signal transduction components with several accessory proteins. H. pylori is unusual in that it lacks a methylation-based adaptation system and produces multiple CheV coupling proteins. Chemoreceptors in these bacteria contain nonconserved ligand binding domains, with several chemoreceptors matched to environmental signals. Together, these mechanisms allow for swimming motility that is essential for colonization.
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The Human Gut Microbiome: Ecology and Recent Evolutionary Changes
Jens Walter, and Ruth LeyVol. 65 (2011), pp. 411–429More LessThe human gastrointestinal tract is divided into sections, allowing digestion and nutrient absorption in the proximal region to be separate from the vast microbial populations in the large intestine, thereby reducing conflict between host and microbes. In the distinct habitats of the gut, environmental filtering and competitive exclusion between microbes are the driving factors shaping microbial diversity, and stochastic factors during colonization history and in situ evolution are likely to introduce intersubject variability. Adaptive strategies of microbes with different niches are genomically encoded: Specialists have smaller genomes than generalists, and microbes with environmental reservoirs have large accessory genomes. A shift toward a Neolithic diet increased loads of simple carbohydrates and selected for their increased breakdown and absorption in the small intestine. Humans who outcompeted microbes for the new substrates obtained more energy from their diets and prospered, an evolutionary process reflected in modern population genetics. The three-way interactions between human genetics, diet, and the microbiota fundamentally shaped modern populations and continue to affect health globally.
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Approaches to Capturing and Designing Biologically Active Small Molecules Produced by Uncultured Microbes
Vol. 65 (2011), pp. 431–453More LessBacteria are one of the most important sources of bioactive natural products for drug discovery. Yet, in most habitats only a small percentage of all existing prokaryotes is amenable to cultivation and chemical study. There is strong evidence that the uncultivated diversity represents an enormous resource of novel biosynthetic enzymes and secondary metabolites. In addition, many animal-derived drug candidates that are structurally characterized but difficult to access seem to be produced by uncultivated, symbiotic bacteria. This review provides an overview about established and emerging techniques for the investigation and exploitation of the environmental metabolome. These include metagenomic library construction and screening, heterologous expression, community sequencing, and single-cell methods. Such tools, the advantages and shortcomings of which are discussed, have just begun to reveal the full metabolic potential of free-living and symbiotic bacteria, providing exciting new avenues for natural product research and environmental microbiology.
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Epidemiological Expansion, Structural Studies, and Clinical Challenges of New β-Lactamases from Gram-Negative Bacteria
Karen Bush, and Jed F. FisherVol. 65 (2011), pp. 455–478More Lessβ-Lactamase evolution presents to the infectious disease community a major challenge in the treatment of infections caused by multidrug-resistant gram-negative bacteria. Because over 1,000 of these naturally occurring β-lactamases exist, attempts to correlate structure and function have become daunting. Although new enzymes in the extended-spectrum β-lactamase (ESBL) families are frequently identified, the older CTX-M-14 and CTX-M-15 enzymes have become the most prevalent ESBLs in global surveillance. Carbapenemases with either serine-based or zinc-facilitated hydrolysis mechanisms are posing some of the most critical problems. Most geographical regions now report KPC serine carbapenemases and the metallo-β-lactamases VIM, IMP, and NDM-1, even though NDM-1 was only recently identified. The rapid emergence of these newer enzymes, with multiple β-lactamases appearing in a single organism, makes the design of new β-lactamase inactivators or β-lactamase-stable β-lactams all the more difficult. Combination therapy will likely be required to counteract the continuing evolution of these insidious enzymes in multidrug-resistant pathogens.
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Gene Regulation in Borrelia burgdorferi
Vol. 65 (2011), pp. 479–499More LessBorrelia burgdorferi, the spirochete that causes Lyme disease, is maintained in nature via an enzootic cycle that comprises a tick vector and a vertebrate host. Transmission from the tick to the mammal, acquisition from the mammal back to the tick, and adaptation to the two disparate environments require sensing signals and responding by regulating programs of gene expression. The molecular mechanisms utilized to effect these lifestyle changes have begun to be elucidated and feature an alternative sigma factor cascade in which RpoN (σ54) and RpoS (σS) globally control the genes required for the different phases of the enzootic cycle. The RpoN-RpoS pathway is surprisingly complex, entailing Rrp2, an unusual enhancer-binding protein and two-component regulatory system response regulator activated by acetyl phosphate; BosR, an unorthodox DNA-binding protein; DsrABb, a small noncoding RNA; and Hfq and CsrA, two RNA-binding proteins. B. burgdorferi also has a c-di-GMP signaling system that regulates the tick side of the enzootic cycle and whose function is only beginning to be appreciated.
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Biology of Clostridium difficile: Implications for Epidemiology and Diagnosis
Vol. 65 (2011), pp. 501–521More LessClostridium difficile is an anaerobic, spore-forming, gram-positive rod that causes a spectrum of antibiotic-associated colitis through the elaboration of two large clostridial toxins and other virulence factors. Since its discovery in 1978 as the agent responsible for pseudomembranous colitis, the organism has continued to evolve into an adaptable, aggressive, hypervirulent strain. Advances in molecular methods and improved animal models have facilitated an understanding of how this organism survives in the environment, adapts to the gastrointestinal tract of animals and humans, and accomplishes its unique pathogenesis. The advances in microbiology have been accompanied by some important clinical observations including increased rates of C. difficile infection, increased virulence, and multiple outbreaks. The major new risk is fluoroquinolone use; there is also an association with proton pump inhibitors and increased recognition of cases in outpatients, pediatric patients, and patients without recent antibiotic use. The combination of more aggressive strains with mobile genomes in a setting of an expanded pool of individuals at risk has refocused attention on and challenged assumptions regarding diagnostic gold standards. Future research is likely to build upon the advancements in phylogenetics to create novel strategies for diagnosis, treatment, and prevention.
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Interactions of the Human Pathogenic Brucella Species with Their Hosts
Vol. 65 (2011), pp. 523–541More LessBrucellosis is a zoonotic infection caused primarily by the bacterial pathogens Brucella melitensis and B. abortus. It is acquired by consumption of unpasteurized dairy products or by contact with infected animals. Globally, it is one of the most widespread zoonoses, with 500,000 new cases reported each year. In endemic areas, Brucella infections represent a serious public health problem that results in significant morbidity and economic losses. An important feature of the disease is persistent bacterial colonization of the reticuloendothelial system. In this review we discuss recent insights into mechanisms of intracellular survival and immune evasion that contribute to systemic persistence by the pathogenic Brucella species.
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Metabolic Pathways Required for the Intracellular Survival of Leishmania
Vol. 65 (2011), pp. 543–561More LessLeishmania spp. are sandfly-transmitted parasitic protozoa that cause a spectrum of important diseases and lifelong chronic infections in humans. In the mammalian host, these parasites proliferate within acidified vacuoles in several phagocytic host cells, including macrophages, dendritic cells, and neutrophils. In this review, we discuss recent progress that has been made in defining the nutrient composition of the Leishmania parasitophorous vacuole, as well as metabolic pathways required by these parasites for virulence. Analysis of the virulence phenotype of Leishmania mutants has been particularly useful in defining carbon sources and nutrient salvage pathways that are essential for parasite persistence and/or induction of pathology. We also review data suggesting that intracellular parasite stages modulate metabolic processes in their host cells in order to generate a more permissive niche.
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Capsules of Streptococcus pneumoniae and Other Bacteria: Paradigms for Polysaccharide Biosynthesis and Regulation
Vol. 65 (2011), pp. 563–581More LessCapsular polysaccharides and exopolysaccharides play critical roles in bacterial survival strategies, and they can have important medical and industrial applications. An immense variety of sugars and glycosidic linkages leads to an almost unlimited diversity of potential polysaccharide structures. This diversity is reflected in the large number of serologically and chemically distinct polysaccharides that have been identified among both gram-positive and gram-negative bacteria. Despite this diversity, however, the genetic loci and mechanisms responsible for polysaccharide biosynthesis exhibit conserved features and can be classified into a small number of groups. In Streptococcus pneumoniae, capsule synthesis occurs by one of two distinct mechanisms that involve the polymerization of either individual sugars in a processive reaction (synthase dependent) or discrete repeat units in a nonprocessive reaction (Wzy dependent). Characterization of these systems has provided novel insights that are applicable to polymers synthesized by many gram-positive and gram-negative bacteria, as well as eukaryotes.
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Synthetic Poliovirus and Other Designer Viruses: What Have We Learned from Them?
Vol. 65 (2011), pp. 583–609More LessOwing to known genome sequences, modern strategies of DNA synthesis have made it possible to recreate in principle all known viruses independent of natural templates. We describe the first synthesis of a virus (poliovirus) in 2002 that was accomplished outside living cells. We comment on the reaction of laypeople and scientists to the work, which shaped the response to de novo syntheses of other viruses. We discuss those viruses that have been synthesized since 2002, among them viruses whose precise genome sequence had to be established by painstakingly stitching together pieces of sequence information, and viruses involved in zoonosis. Synthesizing viral genomes provides a powerful tool for studying gene function and the pathogenic potential of these organisms. It also allows modification of viral genomes to an extent hitherto unthinkable. Recoding of poliovirus and influenza virus to develop new vaccine candidates and refactoring the phage T7 DNA genome are discussed as examples.
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Regulation of Antigenic Variation in Giardia lamblia
Vol. 65 (2011), pp. 611–630More LessAntigenic variation, a clonal phenotypic variation developed by microorganisms, involves the permanent switching of homologous, antigenically different cell surface molecules. In pathogenic microorganisms, antigenic variation is often described as a mechanism to evade the host immune system and therefore is responsible for the generation of chronic and/or recurrent infections. However, antigenic variation has also been involved in expanding host diversity and differential courses of the diseases. The intestinal protozoan parasite Giardia lamblia undergoes antigenic variation through the continuous exchange of approximately 200 variant-specific surface proteins. Here we review the principal issues regarding the significance of antigenic variation during Giardia infections, the particular features of the variant-specific surface proteins, and the current knowledge on the mechanisms that regulate this process, as well as the relevance of disrupting antigenic variation as a novel approach to design effective antiparasitic vaccines.
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Alternative Pathways of Carbon Dioxide Fixation: Insights into the Early Evolution of Life?
Vol. 65 (2011), pp. 631–658More LessThe fixation of inorganic carbon into organic material (autotrophy) is a prerequisite for life and sets the starting point of biological evolution. In the extant biosphere the reductive pentose phosphate (Calvin-Benson) cycle is the predominant mechanism by which many prokaryotes and all plants fix CO2 into biomass. However, the fact that five alternative autotrophic pathways exist in prokaryotes is often neglected. This bias may lead to serious misjudgments in models of the global carbon cycle, in hypotheses on the evolution of metabolism, and in interpretations of geological records. Here, I review these alternative pathways that differ fundamentally from the Calvin-Benson cycle. Revealingly, these five alternative pathways pivot on acetyl-coenzyme A, the turntable of metabolism, demanding a gluconeogenic pathway starting from acetyl-coenzyme A and CO2. It appears that the formation of an activated acetic acid from inorganic carbon represents the initial step toward metabolism. Consequently, biosyntheses likely started from activated acetic acid and gluconeogenesis preceded glycolysis.
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Previous Volumes
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Volume 77 (2023)
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Volume 74 (2020)
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Volume 71 (2017)
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Volume 65 (2011)
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