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activate their effectors, indicating the bacterial effectors have developed a novel
way to manipulate these host proteins.
Other cytoskeletal components (MT and IF)
The T3SS effector VirA was initially identified as being required for the efficient
entry of bacteria into epithelial cells (
Uchiya et al., 1995
) and was subsequently
demonstrated to be able to destabilize microtubules producing membrane ruffles
and Rac1 activation (
Yoshida et al., 2002
). Further investigation suggested VirA
had protease activity and could selectively degrade α-tubulin allowing intracel-
lular and intercellular spreading (
Yoshida et al., 2006
). Recently VirA was shown
not to directly degrade tubulin or microtubules (
Davis et al., 2008
;
Germane
et al., 2008
) and the mechanism of microtubule disruption remains unclear. The
VirA homolog EspG from EPEC and EHEC was also shown to induce microtu-
bule disruption, releasing GEF-H1 from the cytoskeleton and activating RhoA
resulting in actin stress fiber formation (
Matsuzawa et al., 2004
). New evidence
suggests EspG acts as a Rab GTPase activating protein (RabGAP) trapping Rab
GTPases in their inactive GDP bound form (Dong et al. 2012), in addition to
binding PAKs and ARF GTPases (Selyunin et al., 2011), all of which may have
downstream effects that result in cytoskeletal rearrangements.
EspF interacts with cytokeratin 18 (CK18), a protein that forms part of the
intermediate filament network in epithelial cells and can be seen recruited to
the site of bacterial attachment (
Batchelor et al., 2004
). CK18 can also bind
Tir (
Batchelor et al., 2004
) and the adapter protein 14-3-3 (
Patel et al., 2006
),
which EspF and Tir can also bind (
Viswanathan et al., 2004
). These interactions
potentially allow Tir and EspF to coordinate collapse of the intermediate fila-
ment network with actin redistribution and polymerization.
MANIPULATION OF HOST IMMUNE RESPONSES
Manipulation of the host immune system is a common theme in bacterial infec-
tions and a requirement for successful colonization and dissemination. Bacteria
must evade phagocytosis, modulate cell-intrinsic innate immunity and avoid
autophagy in order to survive and proliferate.
Inhibition of phagocytosis
The first line of host immune defenses involves professional cells such as mac-
rophages, neutrophils, and dendritic cells, which internalize and destroy bac-
teria and other invaders. Phagocytosis is a process by which phagocytic cells
internalize particulate material and is therefore distinct from other forms of
endocytosis such as the vesicular uptake of fluids. Phagocytosis is a multistep
process triggered by the recognition of specific ligands by surface receptors and
local remodeling of the actin cytoskeleton. Well-characterized phagocytic path-
ways involve Fc gamma receptor (FcγR) and complement receptor 3 (CR3) that
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