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Tag words: bacteria, enteric bacteria, microbiology, microbe, Shigella, Shigella dysenteriae, S. dysenteriae, S. flexneri, shigellosis, food poisoning, gastroenteritis, dysentery, enterotoxin, shiga toxin, verotoxin, hemolytic uremic syndrome, HUS.


Kingdom: Bacteria
Phylum: Proteobacteria
Class: Gamma Proteobacteria
Order: Enterobacteriales
Family: Enterobacteriaceae
Genus: Shigella
Species: e.g. S. dysenteriae

Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interest include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Shigella and Shigellosis (page 3)

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The Large Virulence Plasmid of Shigella flexneri

All virulent strains of Shigella flexneri possess a large 220kb plasmid that mediates its virulence properties. This so-called the invasion plasmid has been shown to encode the genes for several aspects of Shigella virulence, including

- Adhesins that are involved in the adherence of bacteria onto the surface of target epithelial cells

- The production of invasion plasmid antigens (Ipa) that have a direct role in the Shigella invasion process

- Transport or processing functions that ensure the correct surface expression of the Ipa proteins

- The induction of endocytic uptake of bacteria and disruption of endocytic vacuoles

- The intra- and inter-cellular spreading phenotypes

- The regulation of plasmid-encoded vir genes

The presence of this plasmid was discovered in the 1980s, after the observation that essentially the entire chromosome of S. flexneri could be transferred to E. coli without reconstituting the virulence phenotype of the donor. However, the ability to invade tissue culture cells was transferred to E. coli by the conjugal mobilization of this plasmid from S. flexneri.  (see below)

Figure 3. Circular map of the large virulence plasmid of Shigella. Outer ring depicts ORFs and their orientations, color coded according to functional category: 1. identical or essentially identical to known virulence-associated proteins (red); 2, homologous to known pathogenesis-associated proteins (pink); 3. highly homologous to IS elements or transposases (blue); 4. weakly homologous to IS elements or transposases (light blue); 5. homologous to proteins involved in replication, plasmid maintenance, or other DNA metabolic functions (yellow); 6. no significant similarity to any protein or ORF in the database (brown); 7. homologous or identical to conserved hypothetical ORFs, i.e., proteins of unknown function (orange); and 8. Tn501 insertion-associated genes (green). The second ring shows complete IS elements. The third ring graphs G+C content, calculated for each ORF and plotted around the mean value for all ORFs, with each value color coded for the corresponding ORF. Scale is in base pairs. The figure was generated by Genescene (DNASTAR). Venkatesan, M.M., et al. Complete DNA Sequence and Analysis of the Large Virulence Plasmid of Shigella flexneri. Infect Immun. 2001 May; 69(5): 3271�3285.

The invasion locus on the virulence plasmid of Shigella is a pathogenicity island-like cluster that consists of 38 ORFs of the ipa-mxi-spa operons within a stretch of 32 kb of the plasmid. Genes within this locus are critical for Shigella invasion of mammalian cells, although certain genes outside this region are required for optimal invasion of tissue culture cells.

Table 1. Virulence-associated Genes and Functions Encoded by the Large Shigella Virulence Plasmid
Gene Protein Product MW Regulatory or effector function
virF 30 kDa positive regulators of the virG and ipa-mxi-spa loci
invA(mxiB) 38 kDa Necessary for invasion (orients ipa gene products in outer membrane
mxiA 76 kDA Same as above
ippI 18 kDa Same as above
ipaB 62 kDa Necessary for invasion: mediates endocytic uptake of shigellae
ipaC 43 kDa Same as above
ipaA 38 kDa Same as above
ipaD 78 kDa Not necessary for invasion (role unknown)
virB 33 kDa positive regulator of the virG and ipa-mxi-spa loci
virG (icsA) 120 kDa assembles actin tails that propel the bacteria through the cell cytoplasm and into adjacent cells
ipaH 60 kDa has 5 alleles; IpaH7.8 facilitates the escape of Shigella from phagocytic vacuoles
ShET2 enterotoxin

Evolution of the Shigella virulence plasmid
Recent genetic analyses suggest that shigellae do not constitute a distinct genus as traditionally believed but rather are within the genus of E. coli, much like the enteric pathogenic E. coli. These analyses indicate that Shigella emerged from E. coli seven or eight independent times during evolution, leading to three clusters of Shigella, each of which contains serotypes from multiple traditional species, and four or five additional forms, each of which contains one traditional serotype. The three main Shigella clusters are estimated to have evolved 35,000 to 270,000 years ago, which predates the development of agriculture and makes shigellosis one of the early infectious diseases of humans.

The defining event each time Shigella arose was almost certainly the acquisition of an historical precursor of the current-day virulence plasmid. The data also suggest that the loss of specific catabolic pathways (inability to utilize lactose and mucate and to decarboxylate lysine), loss of motility, and expansion of O-antigen diversity that are characteristic of Shigella strains occurred more recently than the acquisition of the plasmid.

Since the plasmid was acquired at distinct times, one would predict that differences reflecting the evolution of the plasmid could be obtained by genetic comparison of virulence plasmids of the seven different Shigella evolutionary groups. Subsequent to the acquisition of the virulence plasmid, divergence of Shigella clones from E. coli would involve clonal divergence (accumulation of mutations by base substitution), horizontal transfer of genetic material from other species, and loss of gene sequences that interfere with pathogenicity.

Certain horizontal gene transfer events have been key to the evolution of Shigella. A quintessential feature of Shigella is its ability to invade mammalian cells and access the cell cytoplasm, defining a niche unique among enteric Gram-negative bacteria, with the exception of enteroinvasive E. coli. Thus, the acquisition and evolution of the ipa-mxi-spa pathogenicity island, which encodes all of the genes required for cell invasion and phagolysosomal lysis, permitted a major alteration in pathogenesis. Likewise, the acquisition of virG (icsA), which mediates actin assembly on Shigella, and virF and virB, the regulators of the virG and ipa-mxi-spa loci, were key to the emergence of Shigella. Since all Shigella serotypes contain these loci, they were probably all present on the prototypic virulence plasmid.

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Kenneth Todar has taught microbiology to undergraduate students at The University of Texas, University of Alaska and University of Wisconsin since 1969.

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