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Infection and Immunity, October 2000, p. 5652-5656, Vol. 68, No. 10
Division of Clinical Immunology and
Rheumatology, Department of Medicine,1 and
Department of Microbiology,2 The
University of Alabama at Birmingham, Birmingham, Alabama 35294, and
Biomedical Sciences Research Center "A. Fleming," 16672 Vari, Greece3
Received 8 March 2000/Returned for modification 30 May
2000/Accepted 18 July 2000
C-reactive protein (CRP) is an acute-phase protein with a
well-known association with infection and other inflammatory
conditions. We have shown that expression of human CRP by CRP
transgenic (CRPtg) mice is protective against lethal infection by
Streptococcus pneumoniae, an effect likely mediated by
CRP's ability to bind to this gram-positive pathogen. In the present
study we tested whether CRPtg mice are resistant to infection with
Salmonella enterica serovar Typhimurium, a gram-negative
pathogen that causes the murine equivalent of typhoid fever. CRPtg mice
experimentally infected with a virulent Typhimurium strain lived longer
and had significantly lower mortality than their non-tg littermates.
The greater resistance of CRPtg mice could be attributed to
significantly increased early (0 to 4 h) blood clearance of
salmonellae and significantly decreased numbers of bacteria in the
liver and spleen on day 7 postinfection. In addition, 14 days after
infection with an avirulent Salmonella strain, the serum
titer of anti-Salmonella immunoglobulin G antibodies was
higher in CRPtg than non-tg mice. This study provides unequivocal evidence that CRP plays an important role in vivo in host defense against salmonellae during the early stages of infection. In addition, as the beneficial effect of CRP includes enhancement of the host's humoral immune response, CRP may also contribute indirectly to host
defense during later stages of infection.
During the acute-phase response, the
serum concentration of C-reactive protein (CRP) increases by several
hundredfold in humans and rabbits (13), whereas in mice CRP
increases only modestly (39). CRP is a pentameric protein
exhibiting Ca2+-dependent binding specificity for
phosphocholine (PCh) (37), phosphoethanolamine (PEt)
(31), and certain other ligands (reviewed in reference
1). A variety of activities have been observed in
vitro that are consistent with a role of CRP in host defense. For
example, CRP binds various pathogens, including bacteria
(18) and fungi (28, 29), and promotes their
phagocytosis by human leukocytes. CRP is also a potent activator of the
classical pathway of complement (17), and therefore it can
mediate opsonization of pathogens by complement activation products.
Probably due to the presence of PCh moieties in its cell wall
C-polysaccharide, CRP reacts in vivo with the gram-positive bacterium
Streptococcus pneumoniae. This reactivity was deduced from
bacterial protection studies demonstrating that administration of human
CRP increases survival of mice subsequently infected with S. pneumoniae (16, 20, 40). In contrast, protection was
not observed after administration of human serum amyloid P-component (SAP) (16), an acute-phase protein in mice but not humans.
SAP is structurally similar to CRP and has lectin-like binding
specificity for galactose derivatives (14). SAP also binds
PEt but not PCh (31). Recently, using CRP transgenic (CRPtg)
mice capable of expressing human CRP in an acute-phase manner
(9), we confirmed that CRP plays a significant role in vivo
in host defense against pneumococcal infections (33).
Subsequently we showed that although its protective effect was more
pronounced in mice with an intact complement system, CRP offered
significant protection even to mice that were decomplemented by cobra
venom factor (34).
The gram-negative pathogen Salmonella enterica serovar
Typhimurium induces a disease in mice that is a model for human typhoid fever (6, 10, 12, 24). Like all gram-negative bacteria, serovar Typhimurium has phosphatidylethanolamine in its lipid bilayers;
however, it does not bind CRP in vitro (21). Thus, based on
these in vitro observations, CRP should not be expected to opsonize the
bacterium. Nevertheless, in the present study we show that human CRP
expressed by transgenic mice is protective against low-dose infection
with serovar Typhimurium. These data for the first time extend to
gram-negative bacteria previous observations (33, 34) of
CRP-mediated protection against pathogens.
Mice.
We previously described (33) CRPtg C57BL/6J
congenic mice. These mice carry a 31-kb ClaI fragment of
human genomic DNA comprised of the CRP gene, 17 kb of
5'-flanking sequence, and 11.3 kb of 3'-flanking sequence
(9), and they express high levels of human CRP in serum in
response to injected endotoxin or after infection with pneumococci
(33). C57BL/6J mice are Itys, i.e.,
extremely susceptible to infection with serovar Typhimurium (3, 4,
30), and thus not suitable for infection experiments. In
contrast, DBA/2J mice carry the Ityr allele
(3, 15). To generate CRPtg mice resistant to serovar Typhimurium, we crossed female C57BL/6J CRPtg mice with DBA/2J males
(Charles River Laboratories, Boston, Mass.) to produce CRPtg and non-tg
F1 hybrids. F1s were backcrossed to DBA/2J to
generate F2s. Since the Ityr allele
is dominant, all F2 mice have the
Salmonella-resistant phenotype. F2 mice were
screened for the presence of the CRP transgene using a
previously described PCR method (23). In addition, since DBA/2J mice are C5 deficient (C5D), F2 mice were also
screened for inheritance of the C5 mutant allele by PCR
(38). Finally, due to sexual dimorphism of CRP transgene
expression, which results in higher levels of serum CRP in males
(33, 35), only male mice were used. Mice were housed in
groups of four, fed and watered ad libitum, maintained according to
protocols established by the Animal Resources Program at this
institution, and 10 to 12 weeks old when used in experiments. Non-tg
littermates served as controls.
Bacteria.
Wild-type (virulent) serovar Typhimurium strain
LT2L (rpoS+) (32) and attenuated
(avirulent) recombinant serovar Typhimurium strain BRD-846
(8) were stored as stock cultures at Blood clearance and survival studies.
Groups of CRPtg and
non-tg littermates were infected by i.v. injection of 2 × 101 to 1 × 106 CFU of strain LT2L
suspended in 200 µl of lactate solution. Blood (50 µl) was
collected from the retroorbital sinus at 1, 10, 30, and 240 min after
infection for analysis of early blood clearance of bacteria. Deaths of
mice were recorded at 24-h intervals for a 120-day period after infection.
Quantitation of viable salmonellae in the blood and organs of
mice.
To determine bacteremia, 50 µl of blood was serially
diluted in Ringer's, and aliquots of each dilution were seeded onto
TSA plates. For determination of bacterial load in organs, mice at various stages of infection were killed by cervical dislocation, and
the spleen and liver were removed. Each organ was homogenized in 10 ml
of ice-cold hypotonic (0.01 M, pH 7.2) phosphate buffer to minimize
bacterial multiplication. Aliquots of serially diluted spleen and liver
homogenate were seeded onto TSA plates and incubated at 37°C for
24 h before bacterial colonies were counted.
Measurement of human CRP and mouse SAP.
Serum human CRP and
mouse SAP were measured by enzyme-linked immunosorbent assay (ELISA) as
described (35). The lower limits of detection of human CRP
and mouse SAP were 20 ng/ml and 25 µg/ml, respectively.
Immunization and determination of serum antibodies.
The
humoral response to salmonellae in mice parallels that in human typhoid
fever and is directed against lipopolysaccharide and a number of other
undefined antigens (6, 24). Infection of mice with
attenuated Typhimurium strains elicits a protective immune response
against virulent strains (30), with the advantage that the
host survives infection. Therefore, we used the avirulent strain
BRD-846 (50% lethal dose [LD50], >1010) as
a live vaccine. For immunizations, mice received by oral gavage 7 × 109 CFU of salmonellae, and blood was collected 14 days
later. Serum anti-Salmonella antibody titers were determined
by ELISA as previously described (22) using microtiter
plates coated with whole-cell lysates of the virulent strain LT2L. Goat
anti-mouse immunoglobulin G (IgG)-biotin or goat anti-mouse
IgG2a-biotin followed by avidin-peroxidase (all from Bio-Rad
Laboratories, Richmond, Calif.) and ABTS
[2,2'-azinobis(3-ethylbenzthiazolinesulfonic acid)] were used to
develop the plates. The reported titer of each specimen is the
reciprocal of the serum dilution giving five times higher absorbance
than undiluted (pooled) preimmune serum.
Statistical analyses.
The data presented are from analyses
of results pooled from three separate survival experiments, two
bacterial clearance experiments, four organ localization experiments,
and two immunization experiments. All values are given as mean ± standard error of the mean. Bacteremia data are presented as means of
untransformed counts. Data on the numbers of viable salmonellae in the
liver and spleen are presented as means of log-transformed counts
(log10 CFU). Median survival time (MST) was estimated by
interpolation using survival curves. The Mann-Whitney two-sample rank
test was used to evaluate differences in length of survival among
groups of mice. The Survival of infected mice.
C57BL/6J mice are highly
susceptible to infection with S. enterica serovar
Typhimurium (15, 20, 21, 30), primarily because they are
homozygous for the Itys allele at the
Ity (immunity to Typhimurium) locus on chromosome 1 (also
known as Bcg and Lsh) (26, 27). In
contrast, DBA/2J mice carry the dominant Ityr
allele (3, 15). The primary effect of the Ity
locus and the Nramp 1 (natural resistance-associated protein
1) gene it contains (36) on resistance to salmonellae is the
regulation of growth within relatively nonbactericidal sites in the
liver and spleen. To generate CRPtg and non-tg mice with sufficient resistance to salmonellae to allow comparison of responses to graded
doses of virulent bacteria, we crossed C57BL/6J-CRPtg mice with DBA/2J
mice. Since the Ityr allele is dominant, all
F2 mice used in the reported experiments had the
Salmonella serovar Typhimurium-resistant
phenotype. DBA/2J mice are C5D due to a spontaneous mutation in
exon 7 of the murine C5 gene (38). CRPtg versus
non-tg and C5D versus C5-sufficient F2 progeny were
obtained in the expected Mendelian ratios. All CRPtg and non-tg mice
used for infection experiments were male and C5D.
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Human C-Reactive Protein Is Protective against
Fatal Salmonella enterica Serovar Typhimurium Infection in
Transgenic Mice
and
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
70°C in Todd-Hewitt
broth supplemented with 0.5% yeast extract (Difco Laboratories,
Detroit, Mich.). BRD-846 was derived from an aroA aroD live
oral vaccine strain (8). The Typhimurium strains used for
infecting mice were collected by centrifugation from stationary-phase
broth cultures (grown overnight at 37°C) and washed and resuspended
in Ringer's lactate solution at 4°C. Concentrations of bacteria were
estimated from absorbance at 420 nm (A420 of 1 = 2 × 108 bacteria/ml). Inocula were kept on
ice, and mice were infected intravenously (i.v.) or orally within 5 min
of diluting the bacteria. The density and viability of bacteria were
confirmed by plating on trypticase soy agar (TSA) (Difco).
2 test was used to determine if
differences between the percentages of tg and control mice surviving
infection were significant. Student's t tests were used for
comparisons of pre- and postinjection levels of serum CRP and SAP,
CRPtg and non-tg antibody titers, and CFU per organ. All procedures
used for data analyses were applied using Statview 512+ (Brain Power,
Inc., Calabasas, Calif.) software. A P value of less
than 0.05 was considered significant in all statistical tests.
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
2 test). To determine the extent of
CRP-mediated protection relative to control animals, we repeated the
experiment using mice infected with higher doses. CRP-mediated
protection was still observed after injection of 700 CFU per mouse,
i.e., two of eight tg mice compared to zero of eight control mice
survived infection, and the difference in MST (37 versus 24 days)
persisted (Fig. 1, inset). All mice infected with 6 × 105 CFU died, and there was no appreciable difference
between the MSTs of control and CRPtg mice (n = 6 each)
(Fig. 1, inset).
View larger version (21K):
[in a new window]
FIG. 1.
MST and survival rate of mice infected with S. enterica serovar Typhimurium LT2L. CRPtg and littermate non-tg
mice (6 mice per group) received 20 CFU of salmonellae i.v. on day 0, and deaths were recorded for 120 days postinfection. Compared to
controls, MST of CRPtg mice was more than 2 weeks longer (MST = 52 versus 36 days) and survival rate was significantly increased
(P < 0.05, 2 test). (Inset) MST of
CRPtg and non-tg mice using increasing doses of salmonellae (six to
eight mice per point).
Early blood clearance and dissemination of injected salmonellae. After i.v. injection, most salmonellae are rapidly killed by serum- and cell-mediated bactericidal mechanisms (10, 12). A few bacteria survive internalization by circulating phagocytic cells, and many of these are transported to the liver and spleen, where they take up residence and multiply (10, 12). Thus, the observed CRP-mediated protection against serovar Typhimurium may have involved enhancement of blood bactericidal activity, reduced transport of intracellular bacteria to liver and spleen, or both.
To determine which of these mechanisms is responsible for CRP-mediated protection against serovar Typhimurium, we compared bacteremia in control and CRPtg mice at different times up to 4 h after i.v. challenge, and quantitated the number of viable organisms delivered to the liver and spleen at 4 h. Serum CRP and SAP levels were monitored. As shown in Fig. 2, blood clearance of salmonellae was more efficient in CRPtg than in non-tg mice, i.e., at 4 h CRPtg mouse blood contained 12-fold fewer viable bacteria than blood from controls (P < 0.05, t test). Also, at 4 h the livers and spleens of CRPtg mice harbored two- to threefold fewer bacteria than controls (Fig. 2, inset). Since fewer bacteria are recovered from the spleen and liver of CRPtg than control mice, the increased clearance of salmonellae from the blood of CRPtg mice cannot be attributed to accelerated transport of bacteria to these organs. Rather, the data are consistent with the notion that CRP enhances killing of the blood-borne pathogens. Within 1 min of bacterial challenge and coincident with severe bacteremia, CRP serum levels were lowered significantly below basal values (27 ± 1 µg/ml) and remained significantly lowered for at least 30 min postinfection (P < 0.05, t tests) (Fig. 3). By 4 h, when the majority of bacteria were cleared from the circulation, serum CRP rebounded to approximately preinfection levels. SAP was also transiently, although not significantly, reduced compared to baseline values (360 ± 90 µg/ml) during the initial 30 min after infection, and its levels at 4 h were significantly elevated (P < 0.05, t test). Although a cause-effect relationship may not exist between clearance of bacteria (Fig. 2) and lowering of serum levels of CRP and SAP (Fig. 3), the correlation is consistent with the hypothesis that the two acute-phase proteins are removed from the fluid phase because they bind to the bacteria and mediate their phagocytosis and clearance from the blood.
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|
Persistence of salmonellae in spleen and liver.
The difference
between CRPtg and non-tg controls in numbers of splenic and hepatic
bacteria ascertained at 4 h postinfection (Fig. 2, inset)
persisted and in fact was more pronounced on day 7, even when higher
doses of bacteria were used for infection (Fig.
4). Depending on the dose of salmonellae
injected, the spleens and livers of transgenic mice harbored 6- to
14-fold and 12- to 20-fold fewer bacteria, respectively, than the
spleens and livers of controls.
|
Serum antibody response.
Since humoral immunity is known to
play a significant role in protection of mice from serovar Typhimurium
(10, 19), we tested if CRP-mediated protection might also
involve enhancement of the immune response. As shown in Fig.
5, 14 days after infection with strain
BRD-846, CRPtg mice had higher levels of serum antibody, i.e., their
anti-Salmonella total IgG titer was on average 11-fold higher than that of non-tg mice and their IgG2a antibody titer was
6-fold higher (P < 0.025, t test).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The most significant finding of the present study is that CRPtg mice expressing human CRP exhibit increased resistance to fatal infection with low doses of S. enterica serovar Typhimurium compared to non-tg littermates. The data clearly show that expression of human CRP increases early clearance of i.v. injected bacteria from the blood and reduces dissemination of bacteria to the liver and spleen, allowing CRPtg mice to live longer and survive infection at a higher rate than similarly infected non-tg mice. Furthermore, the specific serum anti-Salmonella antibody response is enhanced in CRPtg mice, which likely also contributes to the observed protective effect. Thus, the host defense function of CRP is not limited to pneumococci, as generally believed, but appears to be wider, extending to at least one gram-negative bacterial pathogen.
In contrast to the present results, demonstrating clearly that endogenously synthesized CRP plays a role in protection of mice from infection with virulent salmonellae, it was reported earlier that passive administration of human CRP failed to protect BALB/c mice from infection with salmonellae (21). We have no direct proof but can offer several explanations for the difference between the results of these two studies. First, BALB/c mice carry the Itys genotype and thus are predicted to be much more susceptible to Salmonella infection (3, 15, 30) than the Ityr hybrids that we employed. Second, in the earlier study, only a single dose of bacteria (2 × 106 CFU) was used (21), and this was twofold higher than the highest dose that we used. At such overwhelming doses, we also failed to observe differences in survival between CRPtg and control mice. Third, in the earlier experiments, mice received only a single injection of human CRP 30 min prior to infection (21). It was ascertained that only 10% of the injected CRP remained in the blood of mice 6 h later and only 2% remained at 24 h, whereas in our experiments the CRP transgene is expressed continuously. The use of a susceptible strain of mice combined with a very high dose of bacteria likely overwhelmed any protective advantage gained by a single injection of CRP.
Despite subsequent reports (2, 25) suggesting that salmonellae express PCh on the surface, binding of CRP to salmonellae could not be detected by using a sensitive radioimmunoassay (21). We also could not detect binding of CRP to salmonellae or to purified Salmonella lipopolysaccharide, using ELISA-based assays (data not shown). Despite these in vitro results, the most likely mechanism for the observed CRPtg-mediated protection is opsonization by human CRP followed by intracellular killing. CRP could opsonize bacteria in vivo directly or indirectly via complement activation products. The observed transient drop in CRP serum concentration immediately after injection of the bacteria (Fig. 3) is certainly consistent with binding of CRP to the bacteria. If that were the case, a likely ligand for CRP would be the PEt polar head group of phosphatidylethanolamine, the main phospholipid of gram-negative bacterial membranes. Questions about access to PEt in the lipid bilayer and about differences between in vitro and in vivo results cannot be answered on the basis of existing information. Nevertheless, it should be pointed out that similar questions can be raised about access of CRP and antiphosphocholine antibodies to PCh residues of the pneumococcal cell wall teichoic acid, particularly since, like serovar Typhimurium, S. pneumoniae does not bind CRP in vitro. Nevertheless, both CRP and anti-PCh antibodies have been shown convincingly to protect mice from experimental pneumococcal infection (4, 5, 16, 40).
A possible role for SAP in the observed protection of mice from Salmonella infection should be entertained. SAP binds PEt with higher avidity than does CRP (31), and similarly to CRP, its serum levels dropped immediately after administration of salmonellae (Fig. 3), suggesting that SAP also bound to the bacteria. Although SAP has not been reported to have opsonic properties, it has been shown to activate complement (13a) and could conceivably mediate opsonization of bacteria by complement activation products. However, there should be no difference between CRPtg and non-tg mice in terms of SAP levels and function, and therefore the observed differences can be attributed solely to CRP.
Our combined data strongly suggest that the protective action of CRP is realized mainly by limiting dissemination of salmonellae during the initial stage of infection. Antibodies directed against salmonellae, which are known to represent a major defense element in mice and humans (10, 19), are probably most effective during later stages of infection, when the antibody concentration in blood reaches protective levels. In this respect, the heightened immune responsiveness of CRPtg mice can be considered a distal CRP protective effect. Like complement (7, 11), CRP might play a role in discriminating among pathogens and enhancing host immune responses to their antigens. This possibility can be further explored by the use of the tg animals used in this study.
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ACKNOWLEDGMENTS |
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This work was supported in part by NIAID grant AI 42183 to A.J.S.
We thank Mark A. McCrory for his assistance during these studies.
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294. Phone: (205) 975-6241. Fax: (205) 934-1564. E-mail: Alex.Szalai{at}ccc.uab.edu.
Present address: Biomedical Sciences Research Center "A.
Fleming," 16672 Vari, Greece.
Editor: R. N. Moore
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Abstract
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Materials and Methods
Results
Discussion
References
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