Biology Reference
In-Depth Information
Innate immune response
LPS and fimbriae of UPEC stimulate the inflammatory response through the
Toll-like receptor 4 (TLR4) pathway and bacterial adherence can initiate cell
death through apoptosis (
Bien et al., 2012
). TLR4 causes infected cells to pro-
duce cytokines leading to an influx of PMNs and exfoliation of the infected
uroepithelium (
Bien et al., 2012
). This leads to activation of NFκB, the secre-
tion of antimicrobial peptides, and synthesis of the chemokines IL-6/IL-8 which
further recruit neutrophils to kill UPEC (
Bien et al., 2012
). The inflammatory
response also leads to the generation of reactive nitrogen and oxygen species
as well as other antimicrobial compounds (
Mulvey et al., 2000
;
Bower et al.,
2005
).
PhoP
PhoP is the response regulator of a conserved two component signal transduc-
tion system in both pathogenic and non-pathogenic genera of the Enterobac-
teriaceae, with PhoQ as the sensor kinase. In both pathogenic and commensal
E. coli
the PhoPQ system regulates a network of genes in response to low Mg
2+
(
Kato et al., 1999
) and acidic pH (
Eguchi et al., 2011
). However, in uropatho-
genic
E. coli
, a deletion mutant of
phoP
is attenuated in the mouse model of
ascending UTI, and when complemented with
phoPQ
on a plasmid, virulence is
restored (
Alteri et al., 2011
). Microarray and phenotypic analysis demonstrates
that the PhoP regulon includes genes that mediate motility, acid tolerance, and
lipopolysaccharide modification. Furthermore, the
phoP
mutant was highly
susceptible to antimicrobial peptides demonstrating that the PhoP regulon is
involved in avoidance of the host innate immune response (
Alteri et al., 2011
).
An energized membrane is essential for all of the phenotypes observed in the
phoP
mutant, suggesting that the PhoP regulon is involved in maintenance of
membrane potential. This is important during pathogenesis, as the host responds
to invading pathogens by producing antimicrobial peptides and an influx of neu-
trophils and macrophages that produce reactive oxygen species and decrease the
pH in an effort to kill bacterial pathogens (
Bower et al., 2005
). The PhoP regu-
lon includes several gene products such as SodC which detoxify the effects of
superoxides, therefore the PhoP regulon represents a bacterial defense system
against the host innate immune response to infection (
Alteri et al., 2011
).
TcpC
The host immune system recognizes bacterial pathogens using Toll-like recep-
tor (TLR) signaling mechanisms that initiate the innate immune response, char-
acterized by release of the cytokines and chemokines that recruit inflammatory
cells to the site of infection. The toll/interleukin-1 receptor domain (TIR) is
essential to the function of TLRs, as mutation of this domain abolishes LPS rec-
ognition. To avoid killing by the inflammatory response, UPEC has evolved a
system to avoid this TLR-mediated response. UPEC express and secrete TcpC,
Search WWH ::
Custom Search