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et al., 2005
;
Handa et al., 2007
). IpgB2, a homolog of IpgB1, mimics the
GTP-bound form of RhoA and triggers formation of actin stress fibers (
Alto
et al., 2006
). IpgD displays phosphatidylinositol 4-phosphatase activity and
induces morphological changes in the infected cell including membrane
blebbing and ruffling at the entry site (
Niebuhr et al., 2002
).
Cell-to-cell spread and autophagy
The
icsA
gene (also known as
virG
), which is encoded outside the 37 kb invasion
region on the
Shigella
virulence plasmid, is an essential virulence determinant.
icsA
encodes a 120 kDa autotransporter protein that is required for motility of
Shigella
inside cells and spread of the bacteria to adjacent cells (
Makino et al.,
1986
;
Bernardini et al., 1989
).
icsA
mutants do not form plaques in confluent
tissue culture cell monolayers (
Figure 7.3
) and are significantly attenuated in
the macaque monkey challenge model (
Sansonetti et al., 1991
). Because of this
latter property,
icsA
mutants have been the basis of many efforts to develop live,
attenuated
Shigella
vaccines (
Alexander et al., 1996
;
Barnoy et al., 2011
).
The IcsA protein is unusual in that it is expressed asymmetrically on the bac-
terial surface, being found predominantly at one pole (
Goldberg et al., 1993
).
Unipolar localization of IcsA imparts directionality of movement to the organ-
ism. IcsA mediates motility by binding host cytoplasmic N-WASP and the Arp2/
Arp3 complex which catalyze polymerization of actin at that end of the bacte-
rium (
Egile et al., 1999
;
Suzuki et al., 2002
). Polymerization of actin monomers
at one end of the bacterium provides the force that drives the organism through
the host cell cytoplasm and into adjacent cells (
Monack and Theriot, 2001
).
Correct unipolar localization of IcsA in
Shigella
is essential for virulence
and is dependent on synthesis of a complete lipopolysaccharide (LPS) (
Sandlin
et al., 1996
). LPS mutants of
Shigella
produce IcsA but fail to confine IcsA
to the pole. As a result IcsA is found uniformly over the cell surface in these
mutants. The protein is still capable of polymerizing actin but actin polymer-
izes around the entire cell rather than localizing to a single pole. Consequently,
movement is restricted as the bacterium becomes encased in a shell of actin.
A plasmid-encoded protease, SopA/IcsP, has been shown to cleave IcsA and is
proposed to play a role in unipolar localization of IcsA (
Egile et al., 1997
;
Shere
et al., 1997
). However
E. coli
and plasmid-cured derivatives of
S. flexneri
trans-
formed with a cloned
icsA
gene localize IcsA normally (
Sandlin and Maurelli,
1999
;
Monack and Theriot, 2001
). These results suggest that IcsA localization
does not require any other virulence plasmid-encoded gene and that motifs
within IcsA itself contain the information that directs the protein to the pole.
IcsA is also targeted by autophagy, a conserved process in eukaryotes with
diverse functions, from nutrient recycling to degradation of defective proteins
and organelles to recognition and elimination of intracellular pathogens (
Ogawa
et al., 2005
;
Ogawa and Sasakawa, 2006
). The autophagy protein Atg5 binds
IcsA thereby inducing the autophagic degradation of
Shigella
. However IcsB, an
effector encoded by the virulence plasmid and secreted by the T3SS, impairs the
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