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mutations (deletion of genes encoding traits expressed by ancestral
E. coli
strains). These insights provide a possible answer to lingering questions of the
relationship of EIEC to
Shigella
and the evolution of these pathogens. The het-
erogeneous characteristics of EIEC are consistent with a polyphyletic history
and reflect the non-clonal origins of these isolates. Moreover, these findings
strongly suggest that the EIEC are not
Shigella
ancestors, or 'missing links.'
Rather, the EIEC clones may be recently evolved pathogens that have not yet
completely adapted to a pathogenic lifestyle and therefore have not fully devel-
oped the
Shigella
phenotype (
Pupo et al., 2000
). This proposal suggests that
expression of the complete
Shigella
virulence phenotype requires not only the
virulence plasmid but also additional modifications to the
E. coli
genome for
optimal transmissibility, fitness in host tissues, and virulence.
Several recent studies have provided evidence of a new pathway of evo-
lution, termed antagonistic pleiotrophy, that fine-tunes pathogen genomes for
maximal fitness and virulence in host tissues. This pathway and the selective
forces that drive its function can be observed in the transformation of commen-
sal
E. coli
to virulent
Shigella
and EIEC pathogens. Following acquisition of
the virulence plasmid and expression of its virulence genes, commensal
E. coli
gained access to new host tissues. However, such a newly evolved pathogen,
which expresses the full complement of ancestral traits as well as virulence
factors, may not be optimally suited for this new pathogenic lifestyle. Selective
pressures encountered in the new environment (within colonocytes) are very
different to those in the ancestral niche (lumen of the colon). In fact, some
ancestral traits may interfere with the expression or function of factors required
for survival within host tissues. Loci encoding these interfering factors are des-
ignated antivirulence genes. Thus, the newly evolved pathogen must inactivate
ancestral antivirulence genes for optimal fitness and virulence. These modi-
fications to the new pathogen's genome are termed pathoadaptive mutations
(
Sokurenko et al., 1999
;
Maurelli, 2007
).
The convergent evolution of the seven
Shigella
lineages and EIEC presents
a unique opportunity for the identification and characterization of antivirulence
genes and pathoadaptive mutations in addition to the study of pathogen evolu-
tion. Ancestral traits that interfere with virulence are lost from the newly evolved
pathogen genome early on as the increased fitness of the adapted clones reinforces
these beneficial mutations in the newly or recently evolved pathogen population.
Therefore, some traits that are absent in all
Shigella
and EIEC, but commonly
expressed in
E. coli
, are strong indicators of pathoadaptive mutations that have
arisen by convergent evolution. Thus, evidence supporting this new pathogen evo-
lution pathway was first provided in
Shigella
. Lysine decarboxylase (LDC) activ-
ity, which is encoded by the
cadA
gene, is expressed in over 85% of
E. coli
isolates.
In contrast, no isolates of
Shigella
or EIEC express LDC activity (
Silva et al.,
1980
). Lack of LDC activity in
Shigella
and EIEC is consistent with a pathoadap-
tive mutation. Experimental evidence of the antivirulence nature of the
cadA
gene
was provided by the demonstration that the product of LDC activity, cadaverine,
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