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Infect Immun, May 1998, p. 2284-2289, Vol. 66, No. 5
Departments of
Microbiology1 and
Pathology,3 Colorado State University,
Fort Collins, Colorado 80523, and
Department of Medicine,
National Jewish Medical and Research Center, Denver, Colorado
802062
Received 14 November 1997/Returned for modification 9 January
1998/Accepted 24 February 1998
The results of this study to dissect the nature of the acquired
immune response to infection with Listeria monocytogenes in mice with targetted gene disruptions show that successful resolution of
disease requires the essential presence of Listeria monocytogenes is
an intracellular bacterial parasite that, in addition to infecting host
macrophages, can colonize liver hepatocytes and other parenchymal
cells. As a result, the infected host faces both the problem of dealing
with a very rapidly growing pathogen and the problem of sterilizing the
infected tissues.
There is a general consensus that the very early innate response to
infection is mediated by neutrophils (13-16, 47) although at this time NK cells may also play a role (2-5). In the
liver, bacilli are released from parenchymal cells and hepatocytes by lysis by neutrophils and macrophages, with the latter cells becoming activated to a bactericidal state by gamma interferon (IFN- These events are followed by the rapid generation (within 2 to 3 days)
of acquired immunity (44). Although several early reports
pointed to a role by class II-restricted Lyt.2 We have approached this question in a new manner by comparing the
course of listeriosis in mice with gene disruptions (KO). The results
of the study show that IFN-secreting Experimental infections.
Homozygous female mice with
targetted gene disruption of the Histology.
Tissues were fixed in 2% paraformaldehyde,
routinely sectioned, and stained with hematoxylin and eosin. Sections
were read by an experienced veterinary pathologist without prior
knowledge of treatment groups.
Reverse transcription-PCR for cytokine expression in vivo.
Infected tissues were excised, placed in Ultraspec (Cinna/Biotecx,
Friendswood, Tex.), and homogenized, and RNA was extracted as described
previously (17). One microgram of total RNA was reverse
transcribed, diluted, and subjected to PCR expansion of cytokine-specific cDNA. The amount of cytokine-related product was
determined by the exposure of blotted cDNA PCR product to a
fluorescein-tagged target protein sequence-specific probe. The fluorescein was detected by using the enhanced chemiluminescence kit
(ECL; Amersham, Arlington Heights, Ill.), which produces a light signal
that can be detected on film. The number of cycles which generate a
log-linear relationship between the signal on film and the dilution of
the sample was determined empirically, and data were expressed as the
mean pixel value for four samples from four separate mice.
Course of Listeria infection in gene-disrupted
mice.
After intravenous infection, L. monocytogenes
grew progressively in the spleens and livers of control animals for 2 to 4 days, after which time the infection was rapidly cleared, with no
remaining bacteria detected on day 8 (the results of a representative
experiment are shown in Fig. 1). In
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Disruption of the Cellular Inflammatory Response
to Listeria monocytogenes Infection in Mice with
Disruptions in Targeted Genes
ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
T cells and the capacity to elaborate gamma interferon. In the absence of either of
these entities, mice experience increasingly severe hepatitis and
tissue necrosis and die within a few days. The data from this study
support the hypothesis that the protective process is the efficient
replacement of neutrophils in lesions by longer-lived mononuclear
phagocytes; -T-cell-knockout mice died from progressive infection
before neutrophil replacement could occur, whereas in 
-T-cell-knockout mice this replacement process in the liver has
previously been shown to be much slower. In the present study we
attribute this delay to reduced production of the macrophage-attracting chemokine MCP-1 in the -T-cell-knockout animals. These data further support the hypothesis that T cells are important in controlling the inflammatory process rather than being essential to the
expression of protection.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
) production.
T cells
(30, 32-37, 51), evidence slowly accumulated in favor of
the concept that CD8 (Lyt.2+) T cells in fact played the
primary role in resolution of the infection (1, 7, 11, 12, 18, 19,
27, 38, 40, 41, 46). Subsequently, more recent reports have
demonstrated that other -T-cell-negative populations (NK and
T cells) could also contribute to some extent to resistance to
the infection, presumably reflecting their ability to secrete IFN-
(2-6, 8, 23, 26, 39, 50). Whereas some have argued that
this represents a form of compensatory immunity (46), others
have proposed that interactions between T cells and NK cells
comprise a complex regulatory network, preceding and perhaps
influencing or controlling the proliferation of T cells mediating the
-T-cell response (31, 39, 42).
T cells are essential to
disease resolution, a process that relies on the efficient replacement
of an early neutrophil response that if allowed to proceed resulted in
increasingly severe hepatitis and tissue necrosis, with a mononuclear
phagocyte influx that mediated sterilization and prevented further
tissue damage. T cells bearing receptors appear to contribute to
this mechanism by production (or induction) of the macrophage chemokine
MCP-1, which enhances this replacement process.
MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
chain of the T-cell receptor
( KO), the chain ( KO), or the gene encoding IFN- as
well as control C57BL/6 mice were purchased from Jackson Laboratories
(Bar Harbor, Maine) and used when 8 weeks of age. They were infected
intravenously via a lateral tail vein with 2 × 103
L. monocytogenes EGD organisms. The course of the infection
was monitored against time by plating serial dilutions of individual whole-organ homogenates on tryptic soy agar and counting bacterial colony formation after 24 h of incubation at 37°C in humidified air.
RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
-KO mice, no differences were seen in the bacterial load up to
day 4, but after this time the infection resolved more slowly compared
to that in controls (this was particularly evident in the liver; in one
experiment it took 23 days before this organ was devoid of detectable
viable bacteria).
View larger version (22K):
[in a new window]
FIG. 1.
Course of L. monocytogenes infection in
control and KO mice. Data are expressed as mean values
(n = 4); standard errors of the means did not exceed
0.35. ND, no bacterial colonies detected; *, no survivors after day
4. 
, IFN-KO mice; 
, -KO mice; 
, -KO mice; 
,
controls.
-KO mice, despite some evidence of slowing of
the infection in the spleens of these animals.
Histologic appearance of liver tissues. The histologic data obtained for liver samples are summarized in Table 1. In control mice, mild hepatitis seen over the first 2 days increased in severity by day 4, with lesions containing mixtures of macrophages and smaller numbers of neutrophils (Fig. 2). On day 8 small foci of necrosis were still observed, but otherwise the inflammation was decreased. Some neutrophils could still be found, but the infiltrate consisted predominantly of macrophages.
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-KO mice was similar to that in
controls, but these animals showed signs of increasingly severe
necrotizing hepatitis and died after day 4. In these animals neutrophil
infiltration was substantially increased compared with that in
controls. A similar pattern was seen in IFN-KO mice, with an increased
neutrophil infiltration and increasingly severe necrosis.
In -KO mice the pattern was very similar to that in controls,
with mild hepatitis and only scattered small foci of necrosis, but with
fewer macrophages evident on day 4 (Fig. 2). The only major difference
between these mice and control animals was a more-mixed inflammation,
consisting of both macrophages and neutrophils, in the liver on and
after day 8, as previously observed (26).
Cytokine or chemokine message expression in livers of infected
mice.
All four groups of mice produced equivalent amounts of
interleukin 12 (IL-12) in infected tissues (data for the liver are shown in Fig. 3) and, with the exception
of the IFN-KO mice, all produced IFN as would be expected. Tumor
necrosis factor (TNF) message was seen in controls and -KO mice
for the first 2 days, but much lower levels were seen in -KO and
IFN-KO mice.
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-KO and IFN-KO mice leading to hepatitic necrosis
and death of these animals, we examined the early chemokine response in
each group. The generation of macrophage inflammatory protein (MIP)
signals in the -KO and IFN-KO mice was substantially elevated
compared to that in -KO and control mice for the first 4 days,
consistent with the sustained neutrophilia (Fig.
4).
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-KO mice and
increased substantially in controls and IFN-KO mice. On the other hand,
only very low levels of message were observed in the -KO mice
(P < 0.005; -KO mice versus -KO mice).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The results of this study show that mice that are capable of recruiting blood-borne monocytes into sites of infectious inflammation in a timely manner so as to clear and replace shorter-lived polymorphonuclear phagocytes are thus able to curtail the overwise increasing hepatic necrosis and survive an acute L. monocytogenes infection. In animals unable to express this mechanism, an acute necrotic hepatitis proceeds unabated and kills the animal in a few days.
The use of mice with gene disruptions in this study clearly showed that
T cells, but not T cells, were essential to this process,
as was the ability to secrete the cytokine IFN-. In mice lacking
T cells, necrosis in the liver increased progressively, with the
animals dying within 4 to 5 days. An identical pattern was seen for
IFN-KO mice, thus illustrating that this molecule is essential to the
correct expression of antimicrobial immunity. In contrast, in mice
lacking T cells, bacterial clearance was a little slower in the
spleens and livers, with pyogranulomatous lesions occurring in the
latter organ taking longer to resolve, as previously noted by other
laboratories (26, 42). These data therefore indicate that
T cells play an important role in the inflammatory process in
listeriosis but are not essential to animal survival.
The results are consistent with the following hypothesis. The rapidly growing infection generates local tissue damage and results in prostaglandin and vasoactive amine production, triggering a rapid influx of neutrophils. These cells play a protective role (13-16, 47), but they are also short-lived; hence, their accumulation in the liver induces a mild-to-moderate hepatitis causing increasing local necrosis. Lysis of hepatocytes by neutrophils, macrophages, or incoming CD8 T cells will collectively contribute to this necrosis for the first few days of the infection (14-16, 28, 48).
The data are consistent with the hypothesis that the successful
eventual resolution of the infection depends upon the replacement of
this early inflammatory response by a second wave of inflammatory macrophages which destroy remaining bacilli and prevent dissemination. In mice lacking T cells this event does not occur, and so
neutrophil influx and necrosis continue, and the animals die soon
after, most likely from acute hepatitis. In animals lacking T
cells, bacterial clearance from the liver is slower, more neutrophils are seen in lesions (26), and the infection is resolved more slowly. Based on these findings, it seems that both and T
cells in normal animals contribute to control of the inflammatory process.
In normal (-T-cell-positive) mice, macrophages activated by IFN
secrete TNF, which can stimulate local tissue cells to produce a wide
spectrum of chemokines (45), including the macrophage chemoattractant chemokine MCP-1. The current results however tend
to suggest that T cells are either a primary source or a primary
inducer of this material in that -KO mice produced considerably
smaller amounts of mRNA encoding this molecule for the first 4 days of
the infection. The data clearly show that much less MCP-1 is produced
in -KO mice, and therefore it is reasonable to hypothesize that
this is the reason why macrophages replace neutrophils in lesions in
these mice more slowly. In -KO mice, MCP-1 message was still seen
due to the continued presence of T cells, and in fact, the
elevated levels of this chemokine seen early compared to that in
normal, infected mice may suggest some degree of control of
-T-cell MCP-1 production by T cells. In the absence of
these latter cells however, the animal clearly cannot control the
progressively growing infection and hence dies from acute hepatitis
before neutrophil replacement with macrophages can begin to take place.
As further evidence for the hypothesis, we have found expression of
MCP-1 mRNA message in -T-cell-cloned cell lines (43).
The data also imply that the putative recruitment of monocytes into
lesions by MCP-1 takes days to develop. There was only a sparse influx
of these cells in -KO mice by day 4, despite the strong MCP-1
message in these mice, at which point the liver necrosis was moderate
to severe. Presumably, the continued presence of neutrophils at this
time was in response to both the infection and the tissue damage caused
by the increasing necrosis.
This model is completely consistent with models for other infectious
diseases, such as tuberculosis, in which the lungs of -KO
infected mice develop pyogranulomatous lesions containing significant
numbers of neutrophils (21), and influenza, in which the
influx of T cells occurs in parallel with the inflammatory response (9, 10). In those models, as in this one, there was
no hard evidence that T cells are essential to protection. As a
result, instead, these data seem collectively to point to a "traffic
cop" role for T cells, in which they promote the influx of
macrophages and reduce neutrophil influx. The most simple explanation
is that this response is directly due to MCP-1 production, which
attracts macrophages which in turn physically prevent further neutrophil influx into the site. Other more subtle possibilities are
that factors released by T cells influence blood vessel adhesion
molecules that reduce neutrophil traffic or somehow dampen local tissue
damage that would otherwise attract these neutrophils. In the absence
of T cells, other local tissue cells produce MCP-1, but as
observed, granulomatous foci are initially smaller and the infection
takes longer to fully resolve.
Others, however, have proposed much-more-complicated mechanisms to
explain the acquired response to L. monocytogenes. Mombaerts et al. (42) have presented data to indicate that both
-KO and -KO mice are fully capable of controlling and
resolving L. monocytogenes infections, whereas Ladel et al.
(39) have suggested that -KO mice are initially even
more resistant to infection than normal control mice, contrary to our
own observation of rapidly fatal infection in -KO animals. In
addition, the latter study (39) also showed that
neutralization of IFN- by infusion of monoclonal antibody for the
first few days only marginally influenced resolution of disease in both
-KO and -KO mice; again, in the present study, the
infection was rapidly fatal in IFN-KO mice. Several other investigators
(20, 49, 54, 55) have reached conclusions similar to ours.
It has been proposed (31, 39, 42) that successful resolution
of listeriosis involves early interactions between T cells and
NK cells and that this regulatory function of T cells then
extends to the emerging -T-cell population, in an
antiproliferative manner. (We have -KO mice in our breeding
colony that are over 18 months old and have shown no evidence of
lymphoproliferative disease, contrary to the idea that T cells
"control" the -T-cell response [31].) In
addition, it has been proposed (53) that the -T-cell
population is in fact the cause of the necrotic lesions in -KO
mice, despite the facts that these lesions eventually resolve in such
animals and that such lesions develop in -KO mice. While such
mechanisms may exist, the similar numbers of bacteria in both controls
and -KO mice in the first few days, as well as an apparently
normal cytokine response and a mild inflammatory response, strongly
support the hypothesis that such mechanisms are minor and not
essential. Furthermore, there is direct photographic evidence that the
influx of cells into liver lesions in these first days is one of
neutrophils (13); lymphocytes are few and scattered, and
large granulocytic lymphocytes (NK like) are rarely seen
(25).
In this regard, there is some evidence (2-5, 22, 39), with one exception (52), that the presence of NK cells may be necessary for resistance to listeriosis, specifically as an "innate" source of IFN, as revealed by experiments in which IFN activation of macrophages can occur in the absence of T cells (4). In addition, however, production of this cytokine by NK cells is then believed to stimulate infected macrophages to begin to produce IL-12 (29, 53). It will be clear, however, that the results of the current study are not in keeping with this latter hypothesis, in that mRNA encoding IL-12 increased for the first 4 days of the infection in similar manners in both controls and IFN-KO mice. This finding strongly suggests that IFN is therefore not essential to subsequent IL-12 production.
In addition, NK cells that also express the CD4 molecule and which
secrete IL-4 have recently been suggested as the underlying inducers of
MCP-1 production very early during L. monocytogenes infection (24). In the current study however, message for
MCP-1 increased more slowly, and if driven by an IL-4-secreting
NK+ CD4+ population, should have been equally
represented in the -KO mice. This was not the case, although the
data cannot discount the possibility that NK cells are needed to drive
MCP-1 production by T cells. Infection of IL-4-KO mice should
help resolve the importance of this mechanism.
That is not to say, however, that results obtained with gene-disrupted mice should not also be interpreted with caution. It is apparent that compensatory mechanisms certainly occur in KO mice, and many of these animals have been derived from backcrosses with other mouse strains that may influence their susceptibility. Finally, the failure of others to observe the mortality seen in certain KO mice in the current study may reflect their use of an inoculum of bacteria that may have been much less virulent than that used here.
Having said that, our data support the hypothesis that it is a response
by IFN--secreting T cells that is critical to host survival
to listeriosis and that this mechanism, in addition to activation of
infected macrophages, has as an essential component the efficient
replacement of the early neutrophil response by a mononuclear cell
influx, preventing an otherwise fatal progression of tissue damage,
continued neutrophil infiltration and degeneration, and hepatic
necrosis. The data support the concept that T cells play an
important role in this process by producing chemokines that enhance
this replacement process.
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ACKNOWLEDGMENTS |
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This work was supported by NIH grant AI-44808 and a postdoctoral fellowship from the Arthritis Foundation (to A.M.).
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Microbiology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-6011. Phone: (970) 491-5777. Fax: (970) 491-5125. E-mail: iorme{at}vines.colostate.edu.
Editor: R. E. McCallum
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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