Uropathogenic Escherichia coli - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 281

a homolog of the TIR domain ( Cirl et al., 2008 ). TcpC reduces secretion of
the cytokines TNFα (produced by macrophages) and IL-6 (produced by uro-
epithelial cells) by binding the MyD88 adaptor protein. Further study showed
that TcpC also inhibits TRIF and IL-6/IL-1 signaling pathways, which activate
NFκB and IRF3/7, unlike MyD88 ( Yadav et al., 2010 ), further suppressing the
innate immune response. The avoidance of the innate immune response directly
affects the ability of UPEC to cause pyelonephritis. In the mouse model of
infection, the tcpC mutant was significantly reduced in its ability to colonize the
kidneys as compared to the wild-type strain. Furthermore, the reduction in colo-
nization correlated with a decrease in the formation of kidney abscesses during
infection. Both colonization and abscess formation in the kidneys were restored
upon complementation of tcpC on a plasmid, fulfilling molecular Koch's pos-
tulates ( Cirl et al., 2008 ).
Repression of inflammation: SisA and SisB
SisA and SisB are cytosolic proteins expressed by 70% of uropathogenic E.coli
in vivo ( Lloyd et al., 2009b ) and are encoded by 85% and 22% of pyelonephri-
tis isolates respectively ( Mao et al., 2012 ). While the mechanism of action is
unknown, SisA and SisB suppress the host inflammatory response. In E. coli
CFT073, a double deletion mutant Δ sisA Δ sisB was attenuated in both the blad-
der and kidneys at 6 hours post infection and had significantly more inflam-
matory foci in the kidneys. These foci were more severe than those observed
during infection by wild-type E. coli CFT073. However, by 24 or 48 hours post
infection, the double mutant was no longer attenuated, suggesting that SisA and
SisB are involved in early colonization events in vivo. Furthermore, the double
deletion mutant could be complemented by either SisA or SisB expressed from
a plasmid, demonstrating that these proteins have redundant function ( Lloyd
et al., 2009b ). More work is necessary to determine what host component SisA
and SisB interact with to reduce the inflammatory response during the first 6
hours of infection.
Avoidance of detection: AmpG, WaaL, and Alr
The innate immune system continually samples the human body for pathogen-
associated molecular patterns (PAMPs) by pattern recognition receptors, which
include the TLRs. PAMPs produced by UPEC and commensal E. coli and rec-
ognized by TLRs include LPS, flagella, type 1 and P fimbriae. Once recognized
by a TLR, such as TLR4, a signal transduction cascade leads to the production
of cytokines and chemokines including IL-6 and IL-8. Deletion of three genes,
ampG , waaL , and alr , from the uropathogenic E. coli strain NU14 increased
IL-8 secretion from urothelial cells demonstrating that these genes are involved
in reduction of PAMP recognition. AmpG transports peptidoglycan fragments
from the periplasm back into the cytoplasm, thus reducing the amount of pep-
tidoglycan released into the extracellular milieu that can be recognized by the