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ETEC, but associated with diarrhea caused by
E. coli
. The identification of a
group of pathogens based on the features that are 'not present' often leads to the
inclusion of isolates that truly do not belong together. The phylogeny in
Figure
2.1
demonstrates that the included EAEC isolates are diverse and separated in
the phylogeny, highlighting this diversity.
The best-characterized regulator associated with virulence in EAEC is
AggR; this regulator controls expression of the
aap
gene (encoding dispersin)
(
Sheikh et al., 2002
), the aggregative adherence fimbriae (AAF) (
Nataro et al.,
1993
;
Bernier et al., 2002
), and the
aai
type VI secretion system (
Dudley et al.,
2006
). In addition to these factors, serine protease autotransporters of Entero-
bacteriaceae (SPATEs) are thought to be important in EAEC pathogenesis
(
Boisen et al., 2009
). One study examined the virulence profiles of EAEC from
children in Mali to correlate genomic content with clinical outcomes (
Boisen
et al., 2012
). Through a classification and regression tree analysis (CART), they
concluded that the SepA SPATE associated with intestinal inflammation was
positively correlated (
P
= 0.0006) with diarrhea. These studies examine the
virulence profiles of the pathogen with a preconceived concept of virulence in
mind. In contrast, unbiased genome-wide studies have not been published.
The first EAEC draft genome sequenced was the isolate 101-1 (
Rasko et al.,
2008
). EAEC 101-1 does not possess typical EAEC virulence factors, including
the pAA plasmid. Since then, the genomes of 55989 (
Touchon et al., 2009
),
isolated from an HIV-positive patient in Africa, and the prototypical isolate 042
(
Chaudhuri et al., 2010
), have been sequenced. A global phylogeny demon-
strated that EAEC are phylogenetically diverse, reflecting the fact that the AA
phenotype is encoded by features contained on mobile elements. Surveillance
of EAEC infection is difficult because an accurate diagnosis is based on the AA
phenotype and not a molecular marker.
EAEC was brought to the forefront of public interest due to an outbreak
in Germany in 2011 (
Frank et al., 2011
) that caused ∼3500 hospitalizations,
850 cases of HUS and killed 50 (
Grad et al., 2012
). Although outbreaks of
E. coli
-related HUS in the United States have largely been associated with the
enterohemorrhagic O157:H7 lineage (
Parker et al., 2012
), the German outbreak
isolate was serotyped as O104:H4 (
Frank et al., 2011
); this is the same sero-
type as that of the 55989 EAEC isolate, which had previously been sequenced.
Panels of polymerase chain reaction (PCR) assays indicated that this strain con-
tained Shiga-toxin genes, but also contained several virulence factors, including
pAA,
aggR
, and
aaiC
, associated with EAEC (
Frank et al., 2011
). The rapid
sequencing and public release of sequence data initiated a global crowd-source
analysis of the outbreak isolate (
Rohde et al., 2011
). Although incidents of the
acquisition of the Stx bacteriophage had been reported previously by EAEC
(
Morabito et al., 1998
;
Mellmann et al., 2008
), no cases of widespread sickness
and mortality had been published. A comprehensive comparative analysis of the
genomes from multiple O104:H4 isolates revealed that the apparent hyperviru-
lence of the outbreak isolate was most likely due to the independent acquisition
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