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activation of the membrane-bound ( French et al., 1995 ; Vaandrager et al., 1998 )
cGMP-dependent protein kinase (cGK II or PKG) that in turn phosphorylates
CFTR ( Pfeifer et al., 1996 ; Vaandrager et al., 2000 ).
Several different variants of ST have been described in human strains.
STa (STI) peptides come in two varieties ST-Ia(ST-P) and ST-Ib(ST-H)
( Figure 6.3 b), both of which are plasmid-encoded, typically on transposition
elements. These peptides, as well as a similar native peptides, uroguanylin
and guanylin, both activate GC-C, also known as the STa receptor or STaR
( Chao et al., 1994 ; Giannella and Mann, 2003 ). Both ST1 molecules are
produced as pro-peptides that undergo processing and export into the peri-
plasm. Export of ST1b, and presumably ST1a, through the outer membrane
of E. coli depends on the TolC ( Yamanaka et al., 1998 ) type 1 secretion
system (see Chapter 16). In contrast, STb peptides have also been identified
in human strains of ETEC, but predominately are found in porcine strains,
and do not bind GC-C or activate cGMP, and unlike the STa ( Sack et al.,
1975 ; Levine et al., 1977 ) peptides STb toxins are not as clearly linked to
human illness ( Weikel et al., 1986 ).
EAST1, or EnteroAggregative heat-Stable Toxin ( Savarino et al., 1993 ), has
predicted structural similarity to STI molecules ( Figure 6.3 b), and is encoded
by ast genes residing on mobile elements ( McVeigh et al., 2000 ) of plasmids
in some ETEC strains ( Savarino et al., 1996 ; Yamamoto and Echeverria, 1996 ).
While the functional significance of these genes has yet to be determined, they
do appear to encode a molecule with the capacity to stimulate cGMP production
in vitro. Some strains, such as the prototypical ETEC strain H10407 , encode
LT, ST1a, ST1b, and EAST1 ( Fleckenstein et al., 2010 ) suggesting substantial
functional redundancy in the production of enterotoxins.
Candidate virulence molecules of unknown function
Subtractive DNA hybridization studies ( Chen et al., 2006 ), the completion
of multiple ETEC genomes ( Rasko et al., 2008 ; Crossman et al., 2010 ; Sahl
et al., 2011 ), and proteomic studies ( Roy et al., 2010 ) have identified a variety
of other molecules that may be important in the pathogenesis of ETEC and
provide candidate targets for vaccine development. Studies currently underway
are attempting to examine the utility of some of these molecules ( Harris et al.,
2011 ), and to examine their function.
Summary of ETEC pathogenesis
Our view of the molecular pathogenesis of ETEC has evolved significantly in
the past decade. These organisms are significantly more complex than previ-
ously appreciated. The emerging picture of ETEC pathogenesis (depicted in
Figure 6.4 ) suggests that these pathogens orchestrate the deployment of a
sophisticated array of virulence factors in a series of complex interactions with
the host.
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