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* Infectious Diseases Section, Veterans Affairs Healthcare System, San Diego, CA 92161; and University of California School of Medicine, San Diego, CA 92093;
Division of Infectious Diseases, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and
Section of Infectious Diseases, Boston Medical Center, and Boston University School of Medicine, Boston, MA 01605
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA levels were also lower in LBP
KO than in control mice infected with Salmonella. Since
TNF- can activate PMN, LBP KO mice may have both fewer and less
active PMN in the first few hours after Salmonella are
injected, making LBP KO mice more susceptible. This work confirms the
importance of PMN in resistance to Salmonella infections
and shows that this is facilitated by LBP. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LBP is an acute phase reactant that is made by the liver in response to
IL-1
and IL-6 (9). LBP binds to the lipid A portion of
LPS (10). LPS bound to LBP is 100- to 1000-fold more
potent, as measured by the response of CD14+
cells (11). Thus, LBP can greatly amplify the toxic
potential of LPS. This function for LBP would appear to be paradoxical,
since the acute phase response is generally protective, not harmful, to
the host. Therefore, it is likely that LBP is also of some benefit
during the acute phase of Gram-negative bacterial infections. A number
of protective functions have been identified in vitro. For instance,
LBP can function in vitro as an opsonin for Gram-negative bacteria
(12, 13, 14). However, most Gram-negative pathogens have long
chain polysaccharides on their LPS that may limit the access of blood
proteins to their lipid A, so LBP may not bind efficiently to
pathogenic bacteria (15). High concentrations of
exogenously administered LBP have been reported to protect mice from
lethal septic shock by an unknown mechanism, but it is not likely that
such high levels of LBP are achieved under physiological conditions
(16). LBP can transfer LPS to high density lipoprotein
(HDL) as well as to CD14, and LPS is nearly biologically inactive when
complexed to HDL (17). If this happens in vivo, LBP would
be anti-inflammatory. Since the affinity of CD14 for LPS-LBP is
greater than that of HDL, it is not clear whether the trafficking of
LPS to HDL is a major pathway in vivo. High ratios of LBP to LPS may
also inhibit the binding of LPS to lipid membranes and decrease the
stimulatory effects of LPS on mononuclear cells (18).
To study the in vivo functions of LBP, Jack et al. (19) and Wurfel et al. (20) independently engineered LBP-null mice by nearly identical gene-targeting techniques. While Wurfel et al. (20) found no difference in the survival of control and LBP knockout (KO) mice that had been infected with 5 x 107 CFU Escherichia coli 0111:B4 (D. Golenbock, unpublished observations), Jack et al. (19) reported that LBP-KO mice are more susceptible to Salmonella typhimurium. This was the first evidence that LBP is necessary for innate resistance to infection. That report prompted us to investigate how LBP protects mice against Salmonella infections.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The genetic engineering of LBP-deficient mice was previously described (20). LBP KO mice in the fifth generation of backcross to B6 were screened for the alleles of Nramp1 using PCR of genomic DNA (21). Mice were then bred to be homozygous for the wild-type Nramp1G169 (ItyR) allele on the B6/129 background. The mice were allowed free access to food and water. Control mice were BALB/c.D2 congenics that are homozygous for the wild-type Nramp1G169 from DBA/2 mice (22) and (B6 x 129)F1 (Jackson). The F1 mice have a single wild-type Nramp1, which makes them phenotypically resistant to Salmonella. Mice were raised under specific pathogen-free conditions and were infected when they were 6–10 wk old.
Bacteria
S. typhimurium 14028 and Staphylococcus aureus 502A were obtained from American Type Culture Collection (Manassas, VA). Bacteria were grown overnight at 37°C in trypticase soy broth, then centrifuged for 20 min at 3000 x g, and the pellet was washed in 20 ml pyrogen-free saline. We recentrifuged the bacteria and then resuspended the pellet in pyrogen-free normal saline to an absorbance of 0.65 at 600 A. This suspension was appropriately diluted in sterile saline. To kill the bacteria, we boiled them for 30 min before making the dilution for injection.
Infection
Bacteria were injected i.p. or i.v. in a lateral tail vein in 0.1 ml PBS or orally by gavage in 0.1 ml 0.1 M NaHCO3 (23). Mice were sacrificed at intervals, and the tissues were removed sterilely, homogenized, and then diluted in saline for quantitative cultures as previously described (23). There were six mice in each group per time point.
Cytokine assays
Mice were sacrificed, and the fur was removed from the abdominal
wall. We then injected 3 ml sterile, pyrogen-free saline into the
peritoneal cavity and agitated the mice before sterilely withdrawing
the injected saline with a 23-gauge needle and a syringe. Aspirated
fluid was centrifuged at 250 x g to remove cells, and
the supernatant was frozen at -20°C until assayed. We used ELISA
kits from R&D Systems (Minneapolis, MN) according to manufacturer’s
instructions to measure TNF-, macrophage inflammatory protein-2
(MIP-2), and cytokine-induced neutrophil chemoattractant (KC). TNF-
mRNA in spleen cells was measured using quantitative competitive RT-PCR
as previously described (24). Equal amounts of RNA from
three representative animals in each group were mixed together and
assayed by competitive RT-PCR. Endotoxin levels were measured with a
chromogenic Limulus assay (BioWhittaker, Walkersville, MD).
The lower limit of sensitivity is 0.1 endotoxin units.
LBP assay
LBP was measured in serum and peritoneal exudates (see above) using an ELISA method as previously described (25).
Flow cytometry
Peritoneal washes were briefly chilled on melting ice, and the cells were counted using a Sysmex K-1000 (Baxter Diagnostics, McGaw Park, IL). The fluid was then centrifuged at 250 x g, and the cell pellet was resuspended in PBS without Mg2+ or Ca2+ at 1 x 107 cells/ml. Cells were stained with biotinylated RB6-8C5, a rat monoclonal anti-mouse Ly6g that specifically recognizes polymorphonuclear leukocytes (PMN) (26, 27). Bound Ab was detected with FITC-labeled streptavidin. Cells were analyzed by flow cytometry with a Coulter EPICS Elite (Miami, FL). Total white blood cell (WBC) number was determined by hemocytometer counts. The percentage of RB6-8C5-labeled cells was calculated from the flow data and was multiplied by the total WBC to determine the number of PMN in the peritoneal exudate.
Endotoxin
Salmonella minnesota rough LPS was purchased from List Biologicals and diluted in nonpyrogenic saline for use.
Neutropenia
Mice were injected with 300 µg mAb RB6-8C5. This was a larger dose than previously used (27) because the (B6 x 129)F1 mice were less responsive to this treatment than were BALB/c mice.
Statistics
The numbers of bacteria recovered (CFU) were expressed as the log10, and geometric means were determined. The difference between means was analyzed by two-tailed Student’s t test using the Instat program (GraphPad, San Diego, CA). Kaplan-Meier survival curves were compared using the log-rank Mantel-Cox test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the Kaplan-Meier
survival curves for LBP KO and control BALB/c.D2 and (B6 x
129)F1 mice. The LBP KO mice began to die 4 days
after infection, and 50% of them were dead by day 11, the day before
the first control mice began to die. The difference between the LBP KO
mice and the two control strains was highly significant (by Mantel-Cox
test, p = <0.001). The difference between the two
control strains was not significant (p = 0.23).
Thus, LBP-deficient mice were more susceptible than control mice to
infection with a virulent strain of S. typhimurium. We then
infected LBP KO and B/c.D2 control mice to quantify the number of
bacteria in their livers and spleens 3 days after infection. As shown
in Table I, LBP KO mice had bacterial
counts in those organs that were >10-fold higher than those in
controls, which is consistent with the hypothesis that the higher
mortality of LBP KO mice was due to more rapid growth of the
bacteria.
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). This experiment was repeated
with similar results. Thus, LBP played an important role in resistance
to lethal salmonella peritonitis, but not in resistance to a sublethal
intestinal infection. We also infected mice with 2 x
103 S. typhimurium given i.v. and
found no difference in colony counts in the livers and spleens of the
two groups of mice 1, 3, and 5 days after infection (not shown).
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, LBP levels in uninfected control
mice were at the lower limit of detection in the serum and rose 25-fold
3 days after infection. In contrast, LBP was undetectable in the serum
of infected LBP KO mice 3 days after infection, confirming that the
mutation, which was designed to eliminate the methionine start
sequence, abolished the synthesis of LBP protein under both normal and
acute phase response conditions. In peritoneal fluid LBP was not
detectable in uninfected mice, but rose in control mice to 10.8 ng/ml
by 3 h after infection, and after 6 h to 24.7 ng/ml (Table III). Since LBP was measured in 3 ml of a peritoneal wash, which we
estimated to be a 10- to 50-fold dilution of the ascites fluid, the
actual concentration of i.p. LBP was closer to 100 ng/ml at the earlier
time point. LBP was not detectable in the peritoneal exudate of LBP KO
at any time after S. typhimurium infection. S.
aureus also raised the i.p. level of LBP in normal, but not LBP
KO, mice.
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) and further increased
to >50% by 6 h (not shown). In LPB KO mice there was a mean of
only 0.8% PMN by 3 h after infection. The total number of PMN in
LBP KO mice was only 1.5 x 105 compared
with 1.2 x 106 in the B/c.D2 and 8.5 x
105 in (129 x B6)F1 mice (Fig. 3). Even after 6 h the percentage of
PMN in LBP KO mice was <25% (not shown). In contrast to their
impaired response to Salmonella, LBP KO mice responded
normally to injections of S. aureus and casein (0.2% in
PBS; Sigma, St. Louis, MO), even though there was no i.p. LBP in their
peritoneal exudates under any circumstances. Thus, LBP is not required
for mice to respond to Gram-positive bacteria, and LBP KO mice do not
have a global chemotactic defect.
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, control mice had 10 times more MIP-2
and 50 times more KC in their peritoneal exudates than did LBP KO mice
3 h after Salmonella were injected. However, both
groups of mice had similar concentrations of KC and MIP-2 in the
peritoneal washes after injection of S. aureus and
casein.
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shows the percentage of peritoneal exudate cells that were PMN in mice
injected with either 3 x 103 HK bacteria or
a filtrate of that bacterial suspension. Both stimuli elicited an
exudate that contained 
12% PMN, about half as many as were induced
by live bacteria. Because live bacteria can multiply in the peritoneal
cavity in 3 h, we also injected 3 x
104 HK bacteria and its filtrate, which elicited
a response comparable to that to live bacteria. The filtrate from
3 x 104 S. typhimurium contained
12 endotoxin unit/ml, so the mice received only 1.2 endotoxin units, or
0.2 ng LPS.
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, by 3 h after injection of
104 HK E. coli there was a nearly
equivalent increase in the percentage of PMN in the peritoneal exudate
(from <1 to >25%), and the responses to both HK
Salmonella and HK E. coli were LBP dependent.
Taken together, these results suggested that the exudation of PMN into
the peritoneal cavity was primarily a response to LPS, and that this
response was LBP dependent. To confirm this we first injected 1 ng
Salmonella LPS (Re595) i.p. into (B6 x
129)F1 control mice and LBP KO mice and
determined the percentage of PMN 3 h later (Fig. 6). The LBP KO mice had only 4% PMN
compared with 24% in the controls (p =
<0.01). The concentrations of MIP-2 and KC in LBP KO mice was quite
low compared with that in controls. We found no measurable KC and only
1.4 ± 1.7 µg/ml MIP-2 after LPS injection and only 71 ±
23 µg/ml KC and 66.7 ± 20 µg/ml MIP-2 after injecting
104 HK 14028. These levels are comparable to what
we found in LBP KO mice that were injected with live
Salmonella, but much lower than the levels in normal mice
(Fig. 4
). When we injected Re595 into endotoxin-resistant C3H/HeJ and
control C3H/OuJ mice, they had 8% PMN and 48%, respectively. These
results indicate that the exudation of PMN into the peritoneal cavity
is largely a response to LPS and that the response is dependent on both
LBP and TLR4.
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). However, if we made
the casein-treated mice neutropenic with the rat mAb RB6-8C5, the mice
were not protected. This suggests that PMN were necessary for the
beneficial effect of casein, making it unlikely that some other
proinflammatory response to casein was responsible for the protection
against Salmonella infection.
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in the infected mice because of the importance
of TNF- in response to Salmonella infections
(28) and the recent report by Heinrich et al. that LBP KO
mice could be protected from S. typhimurium by pretreatment
with TNF (29). There was no detectable TNF- (<10
pg/ml) in the peritoneal washes taken from either LBP KO or control
mice 3 and 6 h after injection of 3 x
103 S. typhimurium. We then assessed
the ability of LBP KO mice to make TNF- in response to systemic
infection. Since Heinrich et al. (29) could not detect
circulating levels of TNF in Salmonella-infected mice we
used a quantitative, competitive RT-PCR assay (24) to
measure the amount of TNF- mRNA in the spleens of infected mice.
Uninfected LBP KO and control mice had similar levels of TNF- mRNA
in their spleens (2 x 106 molecules/µg
RNA). On day 3 after i.p. infection splenic TNF- mRNA increased
10-fold above the baseline in control mice. In contrast, there was no
increase in TNF- mRNA in infected LBP KO mice, even though they had
higher bacterial counts and so would be expected to make more TNF-
mRNA (Table V) (24). This
confirms that LBP is important for multiple proinflammatory responses
that are beneficial to mice with Salmonella peritonitis.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine how LBP protects mice against Salmonella
peritonitis we first looked for LBP in peritoneal exudates. By 3 h
after infection normal mice had measurable levels of LBP, but LBP KO
mice had no detectable LBP (Table III). Since LBP was present in the
peritoneum soon after infection, we concluded that it could affect the
local response to Gram-negative infections, possibly by facilitating
the synthesis of chemokines. The very rapid appearance of LBP in the
peritoneum suggests that it may have been made locally and could be
part of the local defenses against infection. There is recent evidence
that type II pneumocytes in the lung can make LBP, and so contribute to
lung defenses (30), and that enteric epithelial cells
secrete LBP when stimulated by proinflammatory cytokines
(31). Similarly, there may be peritoneal cells that
synthesize LBP; this remains to be determined.
We then examined the cellular composition of the peritoneal exudate. Although Jack et al. (19) did not find a difference in cell number or type in the peritoneal exudates of LBP KO and normal mice, they did not analyze the composition of the exudate until 24 h after Salmonella infection. When we looked 3 and 6 h after Salmonella infection, we found that control mice had 10–15 times more PMN in the peritoneal exudates than did LBP KO mice. (We found that LBP also accelerates the influx of PMN in mice with Klebsiella peritonitis (D. Golenbock, unpublished observations).) In contrast, PMN exudation in response to the Gram-positive pathogen S. aureus and the nonspecific stimulant, casein was indistinguishable in LBP KO and control mice. Thus, it appears that LBP mediates acute inflammation in response to Gram-negative bacteria, but not other stimuli.
Since the LBP KO mice had fewer PMN after Salmonella
infection, we predicted that they would also have lower levels of CXC
chemokines in the exudate fluids. Indeed, the levels of two neutrophil
chemokines, KC and MIP-2, were >10–50 times higher in control mice
than in LBP KO mice (Fig. 4). In contrast, there were no significant
differences in KC and MIP-2 levels in response to S. aureus
and casein. These results showed that i.p. LBP plays an important role
in the generation of CXC chemokines in response to Gram-negative, but
not Gram-positive, bacteria. Since HK Salmonella and
E. coli were also chemotactic in an LBP-dependent manner, we
tested the response to purified LPS and found that it was also
chemotactic in an LBP-dependent manner. It is most likely that LBP
facilitates the interaction of LPS with host cells that synthesize and
release chemokines. Vesy et al. (17) have recently shown
that outer membrane blebs from S. typhimurium stimulate
human macrophages to make IL-8, and that LBP enhances the potency of
the blebs 100-fold. It is likely that we have shown the equivalent
response in vivo in mice. In vitro, mouse peritoneal macrophages are
induced to make MIP-2 by as little as 0.1 ng LPS (32), and
we injected only 1 ng LPS i.p.
Having established that LBP promotes acute inflammation in
Salmonella peritonitis, we then showed that this response is
critical for an effective host response to Salmonella
peritonitis. We were able to make LBP KO mice more resistant to this
infection by pretreating them with casein, which established an
exudation of PMN independent of LBP. Casein-pretreated LBP KO mice had
a 10-fold reduction in bacterial counts in their livers and spleens.
Most importantly, casein pretreatment was ineffective in mice that were
simultaneously made neutropenic with the mAb RB6-8C5 (Fig. 7). Thus,
the beneficial effect of casein was due to its chemotactic properties,
not to some other proinflammatory effect.
PMN are the first cells to arrive at sites of infection and are therefore one of the first lines of defense against bacterial infections. PMN are not usually considered to be important in the host defense against Salmonella, as these organisms are adapted to grow inside macrophages. However, we and others have shown that PMN efficiently kill Salmonella in vitro (27, 33), and that neutropenic mice are much more susceptible to Salmonella infections (27, 34, 35). In vivo, PMN could be acting directly to kill some of the injected Salmonella, thereby reducing the inoculum enough to slow the course of infection. PMN could also be acting in synergy with macrophages, releasing O2· from their respiratory burst to combine with macrophage NO to make peroxynitrite, a potent antimicrobial product (36). Alternatively, PMN are also a source of proinflammatory cytokines that could activate macrophages (37). While the exact mechanism of action of PMN in Salmonella infections has not been established, the results of this study provide further evidence for the role of PMN in resistance to Salmonella infections.
PMN are recruited from the circulation by a variety of chemotactic
stimuli that include the complement-derived anaphylatoxins, various
neutrophil-active CXC chemokines, and leukotriene B4 (38).
Many chemotactic signals, LPS, and proinflammatory chemokines can also
activate PMN, as measured by generation of NADPH oxidase and
up-regulation of various surface receptors (39, 40, 41, 42). Since
LBP-LPS can also activate PMN (39), as can
macrophage-derived cytokines such as TNF- (43), it is
possible that LBP KO mice not only had fewer PMN in the peritoneal
cavity, but that these PMN were less activated and thus less
bactericidal.
Although we have not established that KC and MIP-2 are primarily
responsible for PMN exudation in Salmonella peritonitis,
those chemokines have been shown to mediate the inflammatory response
to cecal perforation (44, 45). The source of MIP-2 and KC
in acute peritonitis has not been established. Peritoneal mesothelial
cells can make CXC chemokines in response to TNF- and IL-1, but not
LPS (46), so these were probably not the source of KC and
MIP-2 in our experiments. Peritoneal macrophages or mast cells
(44) can also make TNF- and IL-1, but we were unable to
detect TNF- in the peritoneal exudate. Therefore, we consider it
more likely that either peritoneal macrophages or mast cells made CXC
chemokines after being stimulated by LPS in an LBP-dependent manner
(47, 48).
If PMN are important in defending against Salmonella peritonitis, and LBP-deficient mice have fewer PMN than normal mice in the first few hours after infection, why were the LBP-deficient mice not more susceptible to oral infection? This could be explained by the different sources of CXC chemokines in the peritoneum and the gut. In the gut, mucosal epithelial cells, not macrophages, make CXC chemokines in the intestine during enteric infections (49, 50). Although stimulated cultured intestinal epithelial cells can secrete LBP (31), we found that T84 colonic epithelial cells do not respond to LPS in vitro (49), and neither MD-2 nor CD14 is constitutively expressed on intestinal epithelial cell lines (51, 52).
Since LPS activates NF-
B in macrophages, it induces the expression
of many genes (53, 54). Therefore, since LBP deficiency
impairs these responses, it is difficult to exclude the possibility
that LBP KO mice have relative deficiencies of several cytokines or
chemokines other than KC and MIP-2. TNF- is also required for
resistance to Salmonella (28, 55, 56), so low
levels of this cytokine could contribute to the susceptibility of LBP
KO mice. Indeed, although they could not detect circulating TNF in
infected mice, Heinrich et al. (29) showed that exogenous
TNF protected LBP KO mice from S. typhimurium peritonitis.
Although we could not detect TNF- in the peritoneal wash 3 h
after bacteria were injected i.p., the ELISA may not have been
sufficiently sensitive because our sample was diluted. However, we did
find that Salmonella infection stimulated a 10-fold increase
in TNF- mRNA in the spleens of control mice, but not in LBP KO mice
(Table IV). This difference was particularly striking because LBP KO
mice were more severely infected, and the amount of TNF- mRNA in
spleens is normally proportional to the severity of the
Salmonella infection (24). TNF- can be
released from mast cells, which are abundant in the mouse peritoneum,
and mast cell-derived TNF- plays a critical role in recruiting PMN
to the peritoneum (57). Therefore, i.p. injection of
TNF- may have stimulated PMN chemotaxis (29), just as
casein did in our experiments. Alternatively, mesothelial cells may
have been stimulated by the TNF to make CXC chemokines
(58).
We cannot explain why these LBP KO mice had lower levels of TNF-
mRNA after Salmonella infection but normal levels of
circulating TNF- when injected i.v. with E. coli LPS
(20). LPS on intact bacteria is clearly differently
configured than LPS in suspension and so may interact differently with
LBP and cellular receptors when in suspension. If so, since animals
normally encounter LPS in the context of Gram-negative bacterial
infections, the response of LBP KO mice to Salmonella is
probably more physiologically relevant. It is also possible that subtle
differences in the lipid A structures from E. coli and
S. typhimurium (59) could explain the
apparently contradictory results. For instance, Netea et al.
(60) found that LPS from E. coli and S.
typhimurium were not biologically equivalent when injected into
mice. E. coli LPS caused PMN to accumulate in the lungs,
whereas Salmonella LPS directed PMN primarily to the livers.
They did not examine the role of LBP in those responses. In our
experiments i.p. injections of HK E. coli, HK
Salmonella, and purified LPS provoked equivalent acute
inflammatory responses that were TLR4 and LBP dependent (Fig. 6).
Although the i.p. route of Salmonella infection is not physiological, and so may not be relevant to the pathogenesis of naturally occurring Salmonella infections, it does indicate that LBP plays an important role in Gram-negative peritonitis and probably in other systemic Gram-negative infections. LBP is part of the innate immune system, which has evolved to recognize and respond to the lipid A in LPS, a conserved structure in most Gram-negative bacteria. TLR4 (61) and now LBP have been shown to be required for optimal resistance to Salmonella infections. In the absence of LBP, acute inflammation is delayed, and the host is more susceptible to Gram-negative bacterial infections.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joshua Fierer, Infectious Diseases Section (111F), Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail address: jfierer{at}ucsd.edu
3 Abbreviations used in this paper: TLR4, Toll-like receptor 4; HDL, high density lipoprotein; HK, heat-killed; KO, knockout; LBP, LPS-binding protein; MIP-2, macrophage inflammatory protein-2; PMN, polymorphonuclear leukocyte; WBC, white blood cell; KC, cytokine-induced neutrophil chemoattractant.
Received for publication April 9, 2002. Accepted for publication April 26, 2002.
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 G. Mancuso, A. Midiri, C. Beninati, C. Biondo, R. Galbo, S. Akira, P. Henneke, D. Golenbock, and G. Teti Dual Role of TLR2 and Myeloid Differentiation Factor 88 in a Mouse Model of Invasive Group B Streptococcal Disease J. Immunol., May 15, 2004; 172(10): 6324 - 6329. [Abstract] [Full Text] [PDF]
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 D. D. Bannerman, M. J. Paape, J.-W. Lee, X. Zhao, J. C. Hope, and P. Rainard Escherichia coli and Staphylococcus aureus Elicit Differential Innate Immune Responses following Intramammary Infection Clin. Vaccine Immunol., May 1, 2004; 11(3): 463 - 472. [Abstract] [Full Text] [PDF]
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C. Cheminay, D. Chakravortty, and M. Hensel Role of Neutrophils in Murine Salmonellosis Infect. Immun., January 1, 2004; 72(1): 468 - 477. [Abstract] [Full Text] [PDF]
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D. Heumann, R. Lauener, and B. Ryffel The dual role of LBP and CD14 in response to Gram-negative bacteria or Gram-negative compounds Innate Immunity, December 1, 2003; 9(6): 381 - 384. [Abstract] [PDF]
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S. Knapp, A. F. de Vos, S. Florquin, D. T. Golenbock, and T. van der Poll Lipopolysaccharide Binding Protein Is an Essential Component of the Innate Immune Response to Escherichia coli Peritonitis in Mice Infect. Immun., December 1, 2003; 71(12): 6747 - 6753. [Abstract] [Full Text] [PDF]
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D. D. Bannerman, M. J. Paape, W. R. Hare, and E. J. Sohn Increased Levels of LPS-Binding Protein in Bovine Blood and Milk Following Bacterial Lipopolysaccharide Challenge J Dairy Sci, October 1, 2003; 86(10): 3128 - 3137. [Abstract] [Full Text] [PDF]
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J. Xu, R. Lucas, M. Schuchmann, S. Kuhnle, T. Meergans, A. P. Barreiros, A. W. Lohse, G. Otto, and A. Wendel GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro J. Immunol., July 15, 2003; 171(2): 938 - 947. [Abstract] [Full Text] [PDF]
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B. A. Vallance, W. Deng, K. Jacobson, and B. B. Finlay Host Susceptibility to the Attaching and Effacing Bacterial Pathogen Citrobacter rodentium Infect. Immun., June 1, 2003; 71(6): 3443 - 3453. [Abstract] [Full Text] [PDF]
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, and control (B6 x 129)F1 are represented by 
.
There were 10 mice/group. The differences between the survival curves
for both control groups and LBP KO mice are highly significant at
p < 0.002 (by Mantel-Cox test). The difference
between the two control mice is not significant.
, LBP KO mice. The differences after
injection of S. typhimurium are significant
(p = <0.01), but no other differences are
significant.
