Biology Reference
In-Depth Information
Shiga toxins are classified as belonging to one of two types (or groups),
Stx1 or Stx2, based on their serological neutralization profile; within the two
types there are several subtypes (
Scheutz et al., 2012
). All Shiga toxins are pro-
teins with an AB
5
quaternary structure. The enzymatic Shiga toxin A-subunit
(StxA) has
N
-glycosidase activity, and the five B-subunits (StxB) function to
bind glycolipid cell surface receptors (reviewed in
Thorpe et al. (2002)
). In
addition, these different toxin types share similar operon structures, in which
stxA
is immediately upstream of
stxB
. Despite these similarities, Shiga toxins
of a given type or subtype often have different epidemiological profiles. For
example, although data suggest that O157:H7
E. coli
strains that produce Stx2
but not Stx1 are more likely to be associated with HUS and severe disease in
humans (
Griffin and Tauxe, 1991
;
Boerlin et al., 1999
;
Thorpe et al., 2002
;
Beutin et al., 2008
), not all Stx2 subtypes are associated with HUS in humans.
The genes encoding Shiga toxins generally reside in the late region of either
functional or cryptic lambdoid prophages (
Unkmeir and Schmidt, 2000
;
Schmidt,
2001
), and induction of the phages have been shown to result in a marked
up-regulation of toxin production in both Stx1- and Stx2-expressing STEC (
Wag-
ner et al., 2001, 2002
). Phage induction can be triggered by activation of the SOS
response, a bacterial stress response which is activated by DNA damage (
Little and
Mount, 1982
). Certain antibiotics have been shown to activate this response and
promote transcription of
stx1
and
stx2
genes, production of toxin, and mortality in
laboratory mice (
Walterspiel et al., 1992
;
Kimmitt et al., 2000
;
Zhang et al., 2000
).
Furthermore, during infection, antibiotic-induced bacterial cell lysis may increase
the level of free luminal Stx available for systemic absorption (
Kimmitt et al., 2000
;
Tarr et al., 2005
). Consistent with these notions, antibiotic administration has been
associated with an increased risk of subsequent HUS in some studies (
Bell et al.,
1997
;
Wong et al., 2000
). It has therefore been suggested that administration of
antibiotics, particularly those known to activate the SOS response, should be
avoided for treating STEC infection. However, recent
in vitro
studies suggest that
certain antibiotics that do not induce Stx production in STEC may be worthy of
further study (
Bielaszewska et al., 2012
;
Corogeanu et al., 2012
).
The first step in Stx-mediated intoxication is binding of the B-subunit
pentamer to a glycolipid receptor on the host cell surface (
Figure 5.2
, Step
1). The best-studied Stx receptor is globotriaosylceramide (Gb
3
) (
Jacewicz
et al., 1986
;
Waddell et al., 1988
;
Hoffmann et al., 2010
). Gb
3
bound toxin
is endocytosed (Step 2), and trafficked retrograde through the Golgi appa-
ratus to the endoplasmic reticulum (ER; Step 3;
Sandvig et al., 1992
;
Arab
and Lingwood, 1998
;
Girod et al., 1999
;
Sandvig and van Deurs, 2000
;
Tam
and Lingwood, 2007
). During this process, the A-subunit is proteolytically
cleaved, possibly by furin located in the endosome and/or the trans-Golgi net-
work (
Garred et al., 1995a, b
;
Tam and Lingwood, 2007
). However, it should
be noted that the A-subunit is also sensitive to cleavage by cytosolic calpain
(
Garred et al., 1997
). The resulting A1 fragment remains linked to the A2 frag-
ment via an intra A-subunit disulfide bond (
Garred et al., 1997
), and inves-
tigations into Stx1 suggest the holotoxin remains intact during translocation
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