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an infection through M cells. These specialized cells do not produce microvilli
and are not covered with mucus or glycocalyx. They sample intestinal antigens
which are transcytosed unmodified to underlying lymphoid follicles. In the sub-
epithelium, the bacteria are rapidly ingested by resident macrophages. However,
rather than being killed,
Shigella
escape the phagosome and induce caspase-1
activation and pyroptosis of the infected macrophage (
Zychlinsky et al., 1992
;
Suzuki et al., 2005
). Death of the phagocyte has dual effects as the bacteria are
released unharmed along with the pro-inflammatory cytokine IL-1β that initiates
an inflammatory cascade (
Zychlinsky and Sansonetti, 1997
). Following release
from the macrophage,
Shigella
penetrate colonic epithelial cells through the
basolateral surface via interaction with α5-β1 integrins and CD44 (
Watarai et al.,
1996
). As in the macrophage, internalized bacteria rapidly escape the endosomal
vacuole (
Ray et al., 2010
) and spread to adjacent cells. In contrast to the fate of
the macrophage,
Shigella
actively block induction of apoptosis in epithelial cells
(
Faherty and Maurelli, 2009
). Infection of the colonocytes induces the release of
still more pro-inflammatory cytokines, IL-6 and IL-8 (
Sansonetti et al., 1999
).
The high levels of pro-inflammatory cytokines produced by epithelial cells and
macrophages in response to
Shigella
infection signal the massive recruitment of
polymorphonuclear neutrophils (PMNs), the only cells that are able to kill
Shi-
gella
. Thus a paradox of
Shigella
-host interaction exists: how can the shigellae
be successful pathogens (able to infect new hosts) when the organisms are read-
ily killed and eventually cleared by the massive innate host immune response?
One possible answer has recently been proposed.
The severe signs and symptoms of shigellosis are due to extensive tissue
destruction by the intense inflammatory response. The major effectors of this
damage are PMNs. Inhibition of PMN recruitment to the site of infection using
anti-IL-8 antibodies significantly reduces the severity of symptoms (
Sansonetti
et al., 1999
). PMN degranulation mediates tissue destruction and destabilizes
tight junctions between colonocytes (
Perdomo et al., 1994b
).
Shigella
present
in the intestinal lumen exploit this window of opportunity to gain access to the
subepithelium where the pathogens can begin another round of infection by
invasion of colonocytes through the basolateral surface (
Perdomo et al., 1994a
).
Intracellular bacteria are likely protected from PMN killing. Thus, the initial
focus of infection is amplified through successive rounds of infection made
possible by the activity of PMNs. Amplification of the infection increases the
number of
Shigella
in the infected host and increases the likelihood of suc-
cessful transmission to another host. Consistent with this model, recruitment of
PMNs across the epithelium to the apical side (which faces the intestinal lumen)
requires virulent, invasive
Shigella
(
McCormick et al., 1998
). Recruitment of
PMNs further requires that the bacteria interact with the basolateral membrane
of the epithelial cells, where IL-8 is secreted. Bacteria present on the apical
side do not efficiently invade colonocytes nor do they recruit PMNs.
Shigella
residing within cells (or in the subepithelium) mediate PMN recruitment across
the epithelium to the apical surface in model monolayers in part by inducing
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