Type 3 secretion effectors - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 457

bind IgG and C3bi respectively ( Caron and Hall, 1998 ). Importantly EPEC and
EHEC colonize gut epithelium but remain predominantly extracellular. Indeed
EPEC is able not only to block its own uptake by professional phagocytes ( cis-
phagocytosis), but is able also to inhibit the phagocytosis of IgG-opsonized par-
ticles ( trans -phagocytosis) ( Goosney et al., 1999 ; Celli et al., 2001 ; Quitard
et al., 2006 ). Inhibition of both cis- and trans- phagocytosis is T3SS dependent.
The first T3SS effector to be identified as responsible for inhibition of
phagocytosis was EspF ( Quitard et al., 2006 ; Marches et al., 2008 ). EPEC
espF mutants are phagocytosed by mouse-derived macrophages to the same
extent as EPEC lacking a functional T3SS ( Quitard et al., 2006 ; Marches
et al., 2008 ). The role of EspF in inhibition of phagocytosis seems to be corre-
lated with its ability to inhibit PI3K ( Quitard et al., 2006 ). The antiphagocytic
activity of EspF is due to the N-terminal region that also contains binding
sites for actin, profilin, and SNX9 ( Quitard et al., 2006 ; Alto et al., 2007 ;
Peralta-Ramirez et al., 2008 ). These partner proteins have not been shown to
be involved in antiphagocytosis, but as a specific mechanism for EspF activity
still remains to be elucidated, their involvement cannot be discounted. EspF
was shown to block only cis- and FcγR-dependent phagocytosis ( Marches
et al., 2008 ).
EspB binds the actin-binding domain of multiple myosin family members
( Iizumi et al., 2007 ). Myosins (myosin-1c, -2, -5, -6, and -10) are involved in
phagocytosis as they localize at the phagocytic cup and their inhibition sup-
presses phagocytocis ( Swanson et al., 1999 ). Furthermore, early reports have
shown that tropomysin is recruited at the site of EPEC adherence ( Goosney
et al., 2001 ). Through its interaction with myosins EspB can compete with actin
to bind myosins at the actin-binding domain and may then interfere with myo-
sin-induced phagosome constriction. An internal region of EspB (amino acids
159-218) was identified as responsible for this interaction ( Iizumi et al., 2007 )
and deletion of this region reduced the ability of EPEC to inhibit phagocytosis
but was not required for bacterial adherence or delivery of T3SS effectors point-
ing to a specific role in antiphagocytosis ( Iizumi et al., 2007 ).
A recently identified effector involved in inhibition of phagocytosis is EspH,
which blocks the activation of Rho GTPases by binding DH-PH Rho GEFs
( Dong et al., 2010 ). The impact of EspH on actin cytoskeleton dynamics is
reflected at the level of phagocytosis as Rho GTPases control cytoskeleton
remodeling during FcγR-dependent phagocytosis ( Caron and Hall, 1998 ) and
EPEC espH mutants have a reduced ability to inhibit FcγR-dependent phago-
cytosis ( Dong et al., 2010 ).
Uniquely, EspJ alone can inhibit both FcγR- and CR3-dependent phagocyto-
sis ( Marches et al., 2008 ). EspJ expression appears to only block phagocytosis of
opsonized particles ( trans -phagocytosis) but not self-uptake ( cis - phagocytosis).
Similarly to EspF, translocated EspJ localizes to mitochondria ( Kurushima
et al., 2010 ) but this does not preclude a role for EspJ at the phagocytic cup. The
mechanism by which EspJ blocks phagocytosis is currently unknown.