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Production1
North Shore University Hospital/New York University School of Medicine, Manhasset, NY 11030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-6 were readily detectable
in the serum of CD14-deficient mice injected with live or
antibiotic-killed S. aureus. Surprisingly, the serum
concentration of TNF- in CD14-deficient mice was at least threefold
higher than in control mice after injection of either unencapsulated or
encapsulated S. aureus, suggesting that CD14
down-regulates TNF-. A similar increase in serum TNF- occurred
when CD14-deficient animals were injected with gentamicin-killed
bacteria even though no symptoms of shock were observed. These studies
indicate that CD14, in contrast to its key function in responses to the
Gram-negative bacterium, Escherichia coli 0111, does not
play a prominent role in septic shock induced by S.
aureus, and that the symptoms of S. aureus shock
are not due solely to TNF-. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-6, IL-1) (4) when injected with either LPS or live
E. coli. It has been proposed that CD14 may also be an
important mediator of septic shock caused by Gram-positive bacteria
based on the ability of anti-CD14 mAbs to inhibit the responses of
monocytes/macrophages to Gram-positive cell wall components (7, 8, 9, 10, 11, 12, 13). To
address the role of CD14 in Gram-positive septic shock, the responses
of CD14-deficient mice to Staphylococcus aureus were
compared with normal mice by measuring lethality, bacterial clearance,
and cytokine production. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD14-deficient mice (4) were backcrossed three to six times with C57BL/6J mice (The Jackson Laboratory, Bar Harbor, ME) or with BALB/c (Harlan Sprague-Dawley, Madison, WI). Age- and sex-matched CD14-deficient and control mice of the same strain (C57BL/6J or BALB/c) were used as indicated in the text. All experiments were Institutional Animal Care and Use Committee approved and were performed in compliance with the National Institute of Health and the New York State regulations on animal handling and usage.
Bacteria
Ten different isolates of S. aureus (unencapsulated) were obtained from the clinical microbiology laboratory, North Shore Health Systems (a kind gift of Dr. Christine Ginocchio), from infected patients. S. aureus, strain M, was a gift of Dr. C. Y. Lee (University of Kansas), and was previously shown to be a highly virulent encapsulated strain (14). Analysis using india ink staining confirmed that the strain M isolate contained its capsule while all of the other clinical isolates lacked a capsule (data not shown).
Preparation of S. aureus and injections. S. aureus was cultured in tryptic soy broth (Difco, Detroit, MI) to midlogarithmic phase, harvested by centrifugation (2500 x g, 30 min, 4°C), washed twice with pyrogen-free saline (Baxter Healthcare, Deerfield, IL), and resuspended in saline. The concentration of bacteria was estimated from the absorbance at 530 nm or by fluorescence (LIVE/DEAD kit; Molecular Probes, Eugene, OR) and confirmed by viable CFU counts on agar plates. Antibiotic-killed bacteria were prepared by incubating the washed bacteria in saline containing 800 µg/ml gentamicin (Life Technologies, Gaithersburg, MD) for 2 h at 37°C, followed by two washes in saline and plating on agar plates to confirm the efficiency of the treatment. No viable bacteria were detected in neat samples of gentamicin-treated S. aureus. Mice were injected with bacteria and monitored for their physical signs and death for up to 3 wk.
Determination of the number of bacteria and cytokines in blood and
organs.
Blood samples and organs were collected and processed as described (4).
Bacterial CFU were determined by plating serial 10-fold dilutions on
agar. The concentration of TNF- in mouse serum was measured by
cytotoxicity using WEHI-2F cells, as previously described (15). The
concentration of IL-6 in mouse serum was measured by ELISA (Endogen,
Boston, MA).
Cell wall preparation
The cell walls of the encapsulated S. aureus strain M were prepared as described by De Jonge et al. (16). Briefly, bacteria were grown in 1 L of tryptic soy broth, chilled, and harvested by centrifugation. The bacteria were boiled for 30 min in a 4% SDS solution in saline. The cells, recovered by centrifugation and washed seven times in water, were mixed with baked, acid-washed glass beads and disrupted by vigorous agitation (15 min vortex and 15 min shaking at 540 rpm/min (G24 shaker; New Brunswick Scientific, Edison, NJ)). After an initial centrifugation (10 min at 2000 x g), the supernatant was collected and centrifuged at 27,500 x g for 30 min and the pellet was resuspended in a 100 mM Tris-HCl, pH 7.5, solution supplemented with 10 µg/ml DNase I (Sigma, St. Louis, MO), 50 µg/ml RNase A (Boehringer Mannheim, Indianapolis, IN), and 20 mM MgSO4. The resuspended pellet was then incubated for 90 min at 37°C; CaCl2 (10 mM final concentration) and trypsin (100 µg/ml; EM Laboratories, Elmsford, NY) were added, and the suspension was further incubated for 24 h at 37°C. The enzymes were then inactivated by boiling 15 min in the presence of 1% SDS. This preparation was then washed five times with water, once with 8 M LiCl, once with 100 mM EDTA, twice with water, once with acetone, and six times with water before lyophilization.
Stimulation of peritoneal macrophages
Thioglycolate-elicited peritoneal cells (2 x
106/ml) were incubated for 3 h at 37°C under 5%
CO2 in RPMI-HEPES supplemented with 1% autologous serum in
24-well plates. After removal of nonadherent cells, macrophages were
incubated for 3 h in the presence of increasing concentrations of
cell walls from S. aureus strain M or soluble peptidoglycan
from S. aureus (a gift of R. Dziarski Indiana University
School of Medicine) in 0.5 ml RPMI-HEPES/1% autologous serum
with or without polymyxin B (5 µg/ml; Sigma). The supernatants were
then collected and assayed for TNF- by ELISA, as described below.
Preparation of spleen cells and stimulation with S. aureus
Spleen cells were washed in RPMI supplemented with HEPES (10 mM)
(Life Technologies). Adherent cells were prepared by incubation of
washed spleen cells in tissue culture dishes for 4 h at 37°C in
5% CO2 and removal of nonadherent cells by gently washing
the dishes three times with warm RPMI-HEPES. Whole spleen cells and
adherent cells were cultured in RPMI-HEPES supplemented with 1%
autologous serum. For stimulation, increasing numbers of washed
S. aureus were added to 5 x 106 spleen
cells, followed 30 min later with the addition of gentamicin (100
µg/ml) and further incubation for 3 h at 37°C in 5%
CO2. TNF- was measured in cell-free supernatants by
ELISA using the mAb TN3 19.12 (17) and a polyclonal goat
anti-recombinant murine TNF- (gifts of Dr. Schreiber, Washington
University, St. Louis, MO).
Statistical analyses
Statistical comparisons were made using the Fisher "exact" test (for survival studies) or the two-tailed Mann-Whitney test (all others).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies indicated that cell wall products from
Gram-positive bacteria could stimulate the activation of human and
murine macrophages via CD14. These observations suggested that, as for
E. coli 0111 (4), some of the deleterious effects of
Gram-positive infection leading to shock might be CD14 dependent
(7, 8, 9, 10, 11, 12, 13). To test this hypothesis, CD14-deficient and control mice were
injected with various doses of S. aureus and monitored for
lethality. A panel of 11 different isolates of S. aureus was
used. These consisted of 10 unencapsulated isolates of S.
aureus obtained from infected patients, and one highly virulent
encapsulated isolate, strain M (14). Approximately 12 h following
the injection of a lethal dose of any of the isolates of S.
aureus, both CD14-deficient and control mice showed similar
shocklike symptoms, including ruffled hair, eye exudate, and diarrhea.
A summary of the survival data for CD14-deficient and control mice
injected i.v. with an unencapsulated isolate of S. aureus
(isolate 10) at doses ranging from 2.5 x 106 to
1.5 x 107 CFU/gram body weight is shown in Table I
. There is no increase in
survival rate among the CD14-deficient mice compared with the control
mice. When the encapsulated isolate of S. aureus, strain M,
was similarly tested, there was again no statistically significant
difference in survival between CD14-deficient and control mice,
although the CD14-deficient mice showed a slight trend toward lower
survival. Similar results were obtained when S. aureus was
administered i.p. instead of i.v. (data not shown). These results
indicate that there is no remarkable difference in the survival of
CD14-deficient and normal mice after i.v. or i.p. injection with either
encapsulated or unencapsulated S. aureus.
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CD14-deficient mice have previously been shown to more rapidly
clear the Gram-negative organism, E. coli 0111, than control
mice, resulting in reduced bacterial dissemination (4). Although lack
of CD14 has no effect on survival to a lethal S. aureus
infection, it might, nevertheless, play a role in the clearance of
S. aureus. Accordingly, the number of bacteria in the blood
and tissues of CD14-deficient and control mice infected with
encapsulated or unencapsulated S. aureus was examined. Mice
were injected i.v. with 9 x 106 CFU/g of the
unencapsulated isolate of S. aureus (number 10), and the
number of bacteria present in blood and organs after 6 h of
infection was determined. As shown in Fig. 1, CD14-deficient and control mice had
very similar numbers of S. aureus in their blood, liver, and
spleen. A similar result was obtained with the encapsulated strain of
S. aureus (data not shown). These results indicate that, in
contrast to the effects observed after infection with E.
coli 0111, CD14 does not play a role in the clearance of
S. aureus.
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Previous in vitro studies have shown that Abs to CD14 can inhibit
the release of inflammatory mediators induced by cell wall components
from Gram-positive bacteria (7, 8, 9, 10, 11, 12, 13). To determine whether CD14, despite
no effect on survival or bacterial clearance, might nevertheless play a
role in the in vivo induction of inflammatory cytokines during
infection with a live Gram-positive bacterium, the serum concentrations
of TNF- and IL-6 were measured in CD14-deficient and control mice
after infection with the encapsulated S. aureus strain M or
the unencapsulated S. aureus isolate 10 using the C57BL/6 or
BALB/c background mice, respectively. In keeping with previous reports
(18, 19), the concentration of TNF- in the serum of control animals
was very low or absent (Fig. 2,
a and c). Surprisingly, CD14-deficient animals
produced substantially more TNF- than control mice; animals injected
with either encapsulated or unencapsulated S. aureus
produced at least three times as much TNF- as control animals. In
contrast to the results with TNF-, IL-6 was only slightly elevated
(maximum twofold) in CD14-deficient animals injected with this dose of
strain M (Fig. 2b) as compared with controls; at lower doses
of strain M, there was virtually no difference in IL-6 production (data
not shown), indicating that there is no CD14-dependent IL-6 response to
S. aureus in vivo. Furthermore, no differences in IL-6
expression were detected in animals injected with the high dose of
unencapsulated S. aureus (Fig. 2d).
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production by CD14-deficient and
control mice in response to S. aureus were consistently
observed in multiple experiments. Furthermore, the enhanced TNF-
production by CD14-deficient mice was also observed in vitro; when
spleen cells from CD14-deficient and control mice (C57BL/6) were
incubated with live S. aureus (strain M), culture
supernatants from cells from CD14-deficient mice showed greater levels
of TNF- than culture supernatants from cells from control mice (Fig. 3). Similar results were obtained after a
6-h incubation or when nonadherent spleen cells were removed before
activation (not shown). In contrast, when peritoneal macrophages from
CD14-deficient and control mice were exposed to either purified cell
walls or peptidoglycan from S. aureus, there was a clear
dependence on the presence of CD14 for the production of TNF- (Fig. 4).
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, but not
septic shock
To examine whether cell wall components of Gram-positive organisms
are sufficient to cause shock, CD14-deficient and control mice were
injected with gentamicin-killed unencapsulated (isolate 10) S.
aureus (Fig. 5a) and
monitored for cytokine production, symptoms of septic shock, and
lethality. Gentamicin is a bactericidal antibiotic that acts by
inhibiting protein synthesis without directly altering the bacterial
membrane and its components, leaving an intact cell wall and capsule.
This preparation differs from cell walls prepared by the classical
method particularly in that proteins are not denatured. As can be seen
in Fig. 5a, CD14-deficient animals again produced
substantially more TNF- than control animals, yet in neither case
were gross symptoms of shock (ruffled fur, labored breathing, eye
exudate, diarrhea) or lethality observed, even though the amounts of
TNF- produced were similar to those in the serum of animals injected
with live bacteria. Furthermore, mice injected with the encapsulated
S. aureus showed a response similar to those injected with
the unencapsulated organism (Fig. 5b).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine whether CD14 might play a role in the in vivo response to Gram-positive bacteria, CD14-deficient and control mice were injected with a lethal dose of S. aureus, and the effects on lethality, bacterial clearance, and cytokine production were determined. Surprisingly, no differences were observed between CD14-deficient and control mice. Similar results were obtained with the two different types of S. aureus utilized in these studies, a highly virulent encapsulated form, strain M, which has a very large polysaccharide capsule (type 1) (14), and the more common unencapsulated strain of S. aureus, which is sensitive to phagocytosis. The inability to demonstrate any differences in the gross symptoms of septic shock or death rate in CD14-deficient and control mice is quite distinct from what was observed with the Gram-negative organism, E. coli 0111; there, CD14-deficient mice showed no symptoms of shock or death when exposed to a lethal dose of E. coli 0111.
In addition to the lack of a clear difference in symptoms and death
between CD14-deficient and control mice, there was no indication of
reduced cytokine production by CD14-deficient mice; in fact,
CD14-deficient mice produced more TNF- than control mice when
exposed to live S. aureus (Fig. 2
). This induction of
TNF- could be reproduced by gentamicin-killed organisms (Fig. 5),
suggesting that cell wall components may be responsible for this
response. However, the presence of a capsule (strain M), which has been
shown to inhibit some cell wall-mediated events (22, 23, 24), did not
influence TNF- production, suggesting that the bacterial component
inducing TNF- may not be masked by the capsule. Alternatively, the
TNF--inducing component may be a non-cell wall component that does
not require new protein synthesis.
Although TNF- is produced, its induction is not sufficient to
produce death or symptoms of shock; mice exposed to gentamicin-treated
bacteria produce a similar amount of TNF- as those exposed to live
S. aureus, and yet no death or symptoms of shock were
observed. The inability to observe differences in TNF- production in
response to either live or antibiotic-killed S. aureus
brings into question the physiologic relevance of in vitro studies that
examine the induction of TNF- by Gram-positive cell walls or
products.
The lack of a deleterious role for TNF- in the septic shock response
to Gram-positive organisms may not be surprising in view of the
observation that the introduction of anti-TNF Ab into mice after
infection by live S. aureus actually increases the death
rate (19). Based on these studies, the authors have proposed that low
levels of TNF- may actually be protective against Gram-positive
infections. Indeed, it should be noted that the total amount of
circulating TNF- produced by control or CD14-deficient mice after
infection with S. aureus is 7 to 18 times lower than the
amount produced after infection with E. coli 0111 (Fig. 2a) (4), in which TNF- presumably has a deleterious
effect (25). Whether the protective effects referenced above are due to
such reduced levels of TNF- remain to be determined. Similarly, the
observation by others that heat-killed S. aureus can kill
mice (26) does not contradict our data in which we fail to observe
death with gentamicin-killed S. aureus, since the former
experiments were performed after sensitization with
D-galactosamine, an agent that makes mice hypersensitive to
even very small amounts of TNF-.
The ability of CD14-deficient mice to produce TNF- in response to
live or gentamicin-killed organisms is quite surprising in view of the
proposed role for CD14 in cytokine induction by Gram-positive cell wall
products. It indicates the presence of a non-CD14 receptor that can
respond to Gram-positive components. This receptor is present on
splenic macrophages since such cells from CD14-deficient mice produce
large quantities of TNF- in response to S. aureus (Fig. 3). A similar CD14 independence was seen in the in vitro response of
human monocytes to heat-killed unencapsulated pneumococcus (12).
The increased expression of TNF- in CD14-deficient mice is also
surprising, and suggests a role for CD14 in down-regulating TNF-
responses to Gram-positive organisms. Presumably, a cell wall component
of Gram-positive organisms that is not masked by a capsule is
responsible for this down-regulation, since gentamicin-killed
unencapsulated or encapsulated bacteria show the same effect. Whether
this Gram-positive component is one of the so far proposed ligands of
CD14 (10, 27) or an unrelated component of the bacterium remains to be
determined. Such a mechanism of negative signaling has recently been
described with receptors such as Fc
RII and CD22 (28, 29, 30), and
requires phosphorylation by the protein-tyrosine kinase Lyn (31).
Although the molecular mechanisms used by CD14, a GPI-anchored
glycoprotein (3), to transmit signals into the cell are still unknown,
it is intriguing to note that CD14 has also been shown to coprecipitate
with Lyn (32); however, the molecular mechanisms regulating the
generation of a negative signal by CD14 or an associated signaling
molecule remain to be determined.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Sanna M. Goyert, Division of Molecular Medicine, North Shore University Hospital/NYU School of Medicine, 350 Community Drive, Manhasset, NY 11030. E-mail address:
Received for publication August 26, 1998. Accepted for publication January 19, 1999.
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References |
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B activation and TNF production induced by lipopolysaccharide and group B streptococcal cell walls. J. Immunol. 160:4535. in response to LPS. J. Immunol. 150:5556.[Abstract]
, interleukin-1 and tumour necrosis factor- synthesis during experimental murine staphylococcal infection. FEMS Immunol. Med. Microbiol. 7:145.[Medline]
interferon, tumor necrosis factor, and interleukin-6 in Staphylococcus aureus infection in mice. Infect. Immun. 63:1165.[Abstract]
mediates lethal activity of killed Gram-negative and Gram-positive bacteria in D-galactosamine-treated mice. Infect. Immun. 59:2110.RII-deficient mice. Nature 379:346.[Medline]
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