Shigella and enteroinvasive Escherichia coli: Paradigms for pathogen evolution and host–parasite interactions - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 211

blocks the action of the virulence plasmid-encoded Shigella enterotoxin ( Maurelli
et al., 1998 ) and several other virulence phenotypes ( McCormick et al., 1999 ).
Sequence analysis of the cadA region of four Shigella lineages revealed novel
genetic arrangements that are distinct in each strain examined ( Day et al., 2001 ).
Thus, the inactivation of cadA was accomplished by different mechanisms in each
Shigella strain. Studies in EIEC showed that these strains have mutations in cadC ,
a transcriptional activator, which abolishes LDC activity ( Casalino et al., 2003 ).
These studies demonstrate that each newly evolved Shigella and EIEC clone
increased virulence through the loss of an ancestral trait, LDC. Additional anti-
virulence loci that have been lost or inactivated in Shigella spp. and EIEC include
nadA / nadB ( Prunier et al., 2007 ) and speG ( Barbagallo et al., 2011 ).
MOLECULAR PATHOGENESIS
Hallmarks of virulence
Shigella spp. and EIEC cause disease by overt invasion of epithelial cells in the
large intestine. The clinical symptoms of dysentery can be directly attributed to
the following hallmarks of virulence: induction of diarrhea, invasion of intesti-
nal epithelial cells, multiplication inside these cells, spread from cell to cell, and
stimulation of a strong host inflammatory response ( Figure 7.1 ).
Shigella colonize the small intestine only transiently and cause little tissue
damage ( Rout et al., 1975 ). Production of enterotoxins by Shigella and EIEC
in the small bowel probably results in the diarrhea that generally precedes
onset of dysentery ( Fasano et al., 1995 ; Nataro et al., 1995 ). It is believed
that jejunal secretions elicited by these toxins facilitate passage of the bacteria
through the small intestine and into the colon where they colonize and invade
the epithelium.
Formal and his colleagues demonstrated the essential role of epithelial cell
invasion in Shigella pathogenesis in a landmark study that employed both tissue
culture assays to measure invasion and animal models ( LaBree et al., 1964 ).
They showed that spontaneous colonial variants of S. flexneri 2a that are unable
to invade mammalian cells in tissue culture do not cause disease in monkeys.
Further, they showed the presence of wild-type bacteria within epithelial cells
of the large intestine in experimentally infected animals.
Gene transfer studies using E. coli K-12 donors and S. flexneri 2a recipients
established the third hallmark of Shigella virulence. A S. flexneri 2a recipient
that inherits the xyl-rha region of the E. coli K-12 chromosome retains the abil-
ity to invade epithelial cells but has a reduced ability to multiply within these
cells ( Falkow et al., 1963 ). This hybrid strain fails to cause a fatal infection in
the opium-treated guinea pig model and is unable to cause disease when fed to
rhesus monkeys ( Formal et al., 1965 ). The high frequency of recombinants in
these conjugation experiments also served to confirm the close genetic related-
ness of E. coli and Shigella .