Hybrid and potentially pathogenic Escherichia coli strains - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 331

( Hugot et al., 2001 ; Ogura et al., 2001 ) and the genes ATG16L1 and IRGM ,
involved in intracellular bacterial clearance through autophagy ( Massey and
Parkes, 2007 ; Rioux et al., 2007 ). NOD2/CARD15 stimulation by bacterial
muramyl dipeptide activates various antibacterial responses through NF-κB
and MAP kinase signaling pathways ( Fritz et al., 2006 ). The autophagy con-
stitutes an efficient host innate immune mechanism against intracellular repli-
cation of CD-associated AIEC ( Lapaquette et al., 2010, 2012 ). AIEC may take
advantage of a diminished surveillance function of monocytes with NOD2/
CARD15 polymorphisms, since monocytes expressing CD-associated alleles
showed a reduced early cytokine response to AIEC infection ( Peeters et al.,
2007 ). Similarly, reducing the expression of ATG16L1 or IRGM in IECs abro-
gates autophagy of intracellular AIEC. This effect could not be reversed by
the expression of a CD-associated ATG16L1 variant ( Lapaquette et al., 2010 ).
In agreement, impairing expression of NOD2/CARD15, ATG16L1, or IRGM
in macrophages produces an increase in intramacrophagic AIEC ( Massey and
Parkes, 2007 ). Thus, it is hypothesized that dysfunctional immunological
responses toward intracellular bacteria in susceptible individuals harboring
CD-associated polymorphisms contribute to the persistence of AIEC inside
macrophages ( Lapaquette et al., 2012 ).
Damage
As AIEC lacks typical virulence factors from other intestinal E. coli patho-
gens, the main damage elicited by AIEC colonization is restricted to its abil-
ity to sustain chronic, acute inflammation in CD patients. The reduction in
the abundance and biodiversity of intestinal bacteria (dysbiosis) caused by
E. coli over-representation displaces normal flora species known to possess
anti-inflammatory properties ( Sokol et al., 2008 ). Intramacrophagic AIEC bac-
teria can reside in a large vacuole without inducing cell death. Instead, the bac-
teria induce the aggregation and sometimes fusion of infected macrophages,
to form multinucleated giant cells and subsequent recruitment of lymphocytes
( Meconi et al., 2007 ). A hallmark of AIEC is the induction of pro-inflammatory
TNF-α in infected macrophages ( Glasser et al., 2001 ). AIEC also induces
the production of inflammatory chemokines such as CCL20, as well as IL-8
( Eaves-Pyles et al., 2008 ) and IL-1β and IL-6 ( Carvalho et al., 2008 ). Several
lines of evidence support the role of AIEC in the inflammation of CD. TNF-α
stimulates the expression of the AIEC receptor CEACAM6 in IECs ( Carvalho
et al., 2009 ). Moreover, AIEC, but not a non-pathogenic E. coli K-12 strain,
induced colitis in mice with dextran sulfate sodium-injured colon ( Carvalho
et al., 2008 ) or in mice expressing human CEACAM6 ( Carvalho et al., 2009 ).
In addition, there is evidence that AIEC contribute to intestinal injury, disrupt-
ing the epithelial barrier by affecting tight junctions in CEACAM6-expressing
mice ( Denizot et al., 2012 ).