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Research performed over the last 25 years revealed that a type III secretion system T3SS encoded on a large plasmid is a key virulence factor of Shigella flexneri. The T3SS determines the interactions of S. Some of the translocated effector proteins show novel biochemical activities by which they intercept host cell signal transduction pathways.
An understanding of the molecular mechanisms underlying Shigella pathogenesis will foster the boekema trading options of a safe and efficient vaccine, which, in parallel with improved hygiene, should curb infections by this widespread pathogen. Diarrheal diseases caused by bacterial, viral, or parasitic pathogens are a major public health problem.
Malnutrition and the lack of appropriate medical intervention contribute to the high mortality rate, especially for young children. Species of the genus Shigella are among the bacterial pathogens most frequently isolated from patients with diarrhea. Five to fifteen percent of all diarrheal episodes worldwide can be attributed to an infection with Shigellaincluding 1.
Two-thirds of all episodes and deaths occur in children under 5 years. A recent multicenter study of the epidemiology and microbiology of shigellosis in Asia revealed that the incidence of this disease might even exceed previous estimations, boekema trading options Shigella DNA could also be detected in up to one-third of culture-negative specimens A general trend toward less severe clinical manifestations of shigellosis and fewer fatal cases was observed in this study.
Despite these encouraging observations, the emergence of multidrug-resistant Shigella strains and a continuous high disease incidence imply that shigellosis is an unsolved global health problem Shigellosis boekema trading options an acute intestinal infection, the symptoms of which can range from mild watery diarrhea to severe inflammatory bacillary dysentery characterized by strong abdominal cramps, fever, and stools containing blood and mucus.
The disease is usually self-limiting but may become life-threatening if patients are immunocompromised or if adequate medical care is not available. A combination of oral rehydration and antibiotics leads to the rapid resolution of infection. Currently, there is no protective Shigella vaccine available, but boekema trading options vaccines boekema trading options bacterial boekema trading options or killed or live-attenuated bacteria for boekema trading options are under development and are being tested in different clinical phases Excellent recent reviews provide further information on the clinical symptoms, diagnostics, and treatment of shigellosis and give an overview on the different approaches currently employed to develop a protective Shigella vaccine, Here, we cover recent progress in our understanding of shigellosis on a cellular level and on a molecular level.
Specifically, we focus on the type III secretion system T3SS of Shigella flexnerisecreted effector proteins, and the responses that the effectors elicit from host cells. The bacteria are highly infectious, since as few as 10 to microorganisms are sufficient to cause disease This low infectious dose can at least partially be attributed to the presence of effective acid resistance systems, which enable S.
Furthermore, it was shown that Shigella spp. After passage through boekema trading options stomach and small intestine, the bacteria reach the large intestine, where they establish an infection. Most of the current knowledge on mechanisms underlying Shigella pathogenesis is derived from studies of S. Infection with the invasive pathogen S. To gain access to the intestinal mucosa, S. In the initial phase of infection, S. M cells are specialized epithelial cells ECwhich continuously sample particles from the gut lumen and deliver them to the underlying mucosal lymphoid tissue, where immune responses can be initiated The use of M cells as an entry port is consistent with the in vitro observation that S.
Cellular pathogenesis of Shigella spp. The bacteria evade degradation in macrophages by inducing an apoptosis-like cell death, which boekema trading options accompanied by proinflammatory signaling.
Free bacteria invade the EC from the basolateral side, move into the cytoplasm by vectorial actin polymerization, and spread to adjacent cells. The influx of PMN disintegrates the EC lining, which initially exacerbates the infection and tissue destruction by facilitating the invasion of more boekema trading options.
Ultimately, PMN phagocytose and kill Shigellathus contributing to the resolution of the infection. Both cytokines are critical mediators of the acute and massive inflammatory response elicited by S. However, the role of this cytokine in shigellosis has not been completely elucidated.
Once released from the dying macrophage, S. Nevertheless, this strategy is a double-edged sword, as the invasion of EC also elicits a strong inflammatory response. The Nod1-mediated intracellular surveillance system senses bacterial peptidoglycan fragments released by S.
IL-8 mediates a massive recruitment of polymorphonuclear neutrophil leukocytes PMN to the site of infection Furthermore, recent findings indicate that S. Infiltrating PMN destroy the integrity of the epithelial lining, thus enabling more luminal bacteria to reach the submucosa without the need of M cellsFig. Thus, macrophage killing, destruction of the epithelial layer, and the massive influx of PMN exacerbate the bacterial infection and tissue lesion.
These processes are essential for the development of diarrhea and the characteristic pathology of shigellosis. Ultimately, however, the PMN recruited to the site of infection entrap and kill the bacteria, thereby resolving the infection 29, The activation of macrophages and their protection from S. The severe tissue destruction caused by Shigella spp.
Boekema trading options disturbance of electrolyte homeostasis and changes in membrane transport processes, such as uncontrolled ion and fluid secretion, are typical of diarrheal diseases However, the boekema trading options mechanism underlying the onset of diarrhea during shigellosis is still poorly defined. Notably, Shigella enterotoxin 1 ShET1 and ShET2, which are produced by several Shigella strains, were found to induce fluid secretion into the intestine, thus accounting for the watery phase of diarrhea 70 Moreover, Shiga toxin, which is produced only by Shigella dysenteriae serotype 1, is cytotoxic boekema trading options a variety of cell types and is responsible for the development of vascular lesions in the colon, the kidney, and the central nervous system Due to the high toxicity of Shiga toxin, infections with S.
Even though massive inflammation promotes the initial infection by S. It is becoming increasingly clear that S. The bacteria are facultative intracellular pathogens that show a high specificity for human or primate hosts. The first report on the isolation and characterization of bacteria causing bacillary dysentery, later named Shigellawas published by Kiyoshi Shiga at the end of the 19th century Descriptions of boekema trading options differing strains followed over the next decades, with all of them being closely related to the nonpathogenic bacterium Escherichia coli.
To distinguish the pathogenic strains of high clinical relevance from less-pathogenic or nonpathogenic strains, the genus Boekema trading options was defined based on biochemical, serological, and clinical phenotypes The genus Shigella includes the four species S.
According to variations in their O antigens, the species were further divided into boekema trading options serotypes. Today, this traditional classification is challenged from results obtained boekema trading options comparative genomics.
Several studies using different technical approaches clearly prove that Shigella spp. Boekema trading options sequence divergence between S. This is marginal compared to, e. Moreover, diarrheagenic enteroinvasive E. While EIEC does not completely fulfill the definition of the genus Shigellagenome analysis revealed a closer relationship to Shigella spp. Comparative genomics clearly indicates that Shigella spp. The two different phylogenetic trees of Shigella deduced either from numerical and phenotypic taxonomy or from comparative genomics are shown in Fig.
In the latter, three boekema trading options Shigella clusters, boekema trading options containing strains from the traditionally defined species, are identified. The three main Shigella boekema trading options started to diverge from E. As there is currently no new nomenclature for Shigella that reflects the evolutionary as well as the phenotypic classifications, the traditional nomenclature boekema trading options Shigella is used boekema trading options this boekema trading options.
Phylogenetic trees of Shigella and related enterobacteria. A Classical taxonomy of Shigella spp. B Evolutionary tree of Shigella and nonpathogenic E. The distribution of several E. Adapted from references 57a and with permission from the Society for General Microbiology [United Kingdom] and Elsevier, respectively.
In addition to a reassignment boekema trading options the phylogenetic relationships between Shigella strains, comparative genomics provides insight into the genetic basis of Shigella virulence. The genetic information constituting the phenotypes of Shigella spp. The virulence plasmid is an essential virulence determinant of all Shigella spp. The central element of this machinery is a T3SS. The complete sequences of the virulence plasmids and chromosomes of several Shigella strains including all four species are currently available 30,, Furthermore, the genomes of a strain collection representing all serotypes of Shigella were characterized by comparative genomic hybridization This vast amount of genetic information allows the identification of the successive genetic events that led to the evolution of pathogenic Shigella from nonpathogenic E.
Figure boekema trading options illustrates the events that are considered boekema trading options be most important for the evolution of pathogenic Shigella spp. Genetic events contributing to the evolution of Shigella spp. SRL, Shigella resistance locus.
Modified from reference with permission from Macmillan Publishers Ltd. Bacterial evolution is a dynamic process that is accelerated by the gain of phenotypic traits through the acquisition of genes by horizontal gene transfer between distantly related microorganisms as well as through the loss of genes by boekema trading options The transfer and chromosomal incorporation of large mobile genetic entities carrying boekema trading options or more virulence-associated genes, termed pathogenicity islands PAIare important steps for the rapid boekema trading options of pathogenic bacteria from nonpathogenic progenitors 57 Besides the presence of virulence genes, PAI are characterized by nucleotide composition and codon usage differing from those of the boekema trading options of the genome, a mosaic-like structure, association with mobile genetic elements, and genetic instability, which is reflected by an increased deletion frequency.
Both the Shigella chromosome and the virulence plasmid reflect these dynamics by containing numerous insertion sequences IS and markers of genomic rearrangements 30 Boekema trading options distribution of IS types and the phylogenetic grouping of chromosome- boekema trading options plasmid-encoded genes indicate boekema trading options the Shigella chromosome and the virulence plasmid coevolved 67, Moreover, these findings suggest that the acquisition and transfer of plasmids between the strains were early steps in the diversification from E.
In addition to pathogenicity islands on the virulence plasmid, Shigella pathogenicity islands SHI were identified in the chromosome The presence and genomic localization of SHI differ between Shigella strains and may contribute to the variation of virulence phenotypes A specific virulence function has been determined for only some of these genes. The boekema trading options A-like cytotoxic protease SigA and the enterotoxin ShET1, encoded in SHI-1, were found to induce intestinal fluid accumulation in the rabbit ileal loop model of shigellosis 57071and a role for the serine protease Pic in mucus degradation and tissue invasion was postulated based on in vitro studies Moreover, the SHIencoded aerobactin iron acquisition system was found to contribute to virulence in vivo, and shiA attenuates Shigella -induced inflammation by suppression of T-cell signaling, Table 1 summarizes the SHI virulence factors that were identified and further characterized.