Biology Reference
In-Depth Information
Translocated effectors are responsible for much of the damage to host cells.
The precise number of effectors has not been definitively determined, but cer-
tainly numbers in the dozens (
Tobe et al., 2006
). The set of effectors includes
those that (i) disrupt actin cytoskeleton, resulting in the formation of pedestals
(see above), the disruption of tight junctions and/or microvilli; (ii) interfere
with vesicle trafficking pathways; (iii) induce mitochondrial dysfunction; or
(iv) trigger apoptosis. Given that many effectors are described in some detail
in Chapters 4 and 15 of this volume, in this narrative we give a relatively brief
overview of some of the critical effectors. In addition,
Table 5.3
describes the
in vitro
and
in vivo
functions of many of the EHEC effector proteins, as well as
references to primary literature.
Alteration of host vesicle trafficking pathways
EHEC and other AE pathogens manipulate host vesicle trafficking path-
ways. The effector EspG binds several eukaryotic proteins, including ADP-
ribosylating GTPase (ARF), which regulates Golgi membrane trafficking, the
Golgi matrix protein GM130, and p21-activated kinases (PAKs), which in turn
regulate a wide variety of cellular processes (
Clements et al., 2011
;
Selyunin
et al., 2011b
). Consistent with the hypothesis that EspG functions as a scaffold
to generate a novel signaling complex on the Golgi membrane, EspG local-
izes to Golgi, inhibits endomembrane trafficking, and induces Golgi fragmenta-
tion. NleA inhibits vesicle trafficking between the endoplasmic reticulum and
the Golgi and interacts with the Sec24 subunit of the COPII vesicle complex,
which controls membrane fusion events (
Kim et al., 2007
;
Lee et al., 2008a
;
Thanabalasuriar et al., 2012
). Finally, overexpression of EspF (
E. coli
secreted
protein F) in mammalian cells induces membrane tabulation (
Alto et al., 2007
)
and like EspG, appears to function as a scaffold to generate a novel complex by
targeting more than one eukaryotic target, in this case SNX9, which binds to
membranes and regulates endocytosis, and the actin nucleation promoting fac-
tor N-WASP (
Weflen et al., 2010
).
Disruption of epithelial barrier and absorptive function
Epithelial tight junctions (TJs) serve to separate the luminal and adluminal envi-
ronments as well as the apical membrane and basolateral membrane proteins.
AE pathogens target tight junctions, leading to compromised barrier function
that has been assayed by increased permeability and decreased transepithelial
resistance of polarized monolayers (
Canil et al., 1993
;
Dean and Kenny, 2004
;
Shifflett et al., 2005
;
Guttman et al., 2006a, b
). The functional compromise of
TJs correlates with morphological changes, for example the redistribution of
TJ-associated proteins such as ZO-1, claudin, and occludin (
Simonovic et al.,
2000
;
Roxas et al., 2010
;
Zhang et al., 2010
). Changes in epithelial barrier func-
tion observed during infection of monolayers have also been documented dur-
ing animal infection by
C. rodentium
(
Guttman et al., 2006a
;
Ma et al., 2006
;
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