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Infection and Immunity, September 1999, p. 4720-4724, Vol. 67, No. 9
Department of
Microbiology1 and Division of Clinical
Immunology and Rheumatology,2 University of
Alabama at Birmingham, Birmingham, Alabama 35294
Received 15 March 1999/Returned for modification 12 May
1999/Accepted 30 June 1999
Pneumococcal surface protein A (PspA) is a surface-exposed protein
virulence factor for Streptococcus pneumoniae. In this study, no significant depletion of serum complement was observed for
the serum of mice infected with pneumococci that express PspA. In
contrast, in mice infected with an isogenic strain of pneumococci lacking PspA, significant activation of serum complement was detected within 30 min after infection. Also, the PspA-deficient strain but not
the PspA-expressing strain was cleared from the blood within 6 h.
The contribution of PspA to pneumococcal virulence was further
investigated by using mice deficient for C5, C3, or factor B. In mice
deficient for C3 or factor B, PspA-negative pneumococci became fully
virulent. In contrast, in C5-deficient mice as in wild-type mice,
PspA-deficient pneumococci were avirulent. These in vivo data suggest
that, in nonimmune mice infected with pneumococci, PspA interferes with
complement-dependent host defense mechanisms mediated by factor B. Immunoblots of pneumococci opsonized in vitro suggested that more C3b
was deposited on PspA-negative than on PspA-positive pneumococci. This
was observed with and without anticapsular antibody. Furthermore,
processing of the Streptococcus pneumoniae
is a major cause of morbidity and mortality worldwide. Annually in the
United States, there are at least 40,000 deaths due to pneumococcal
infection, primarily among the elderly (10). S. pneumoniae causes otitis media in children and sepsis in patients
infected with the human immunodeficiency virus (14). One of
the virulence factors associated with this organism is pneumococcal
surface protein A (PspA). The role of PspA in virulence has been
demonstrated elsewhere with strains of pneumococci in which
pspA genes have been either deleted or inactivated
(22). Mutant strains not able to make PspA are cleared more
rapidly from the blood of nonimmunized mice than are PspA-producing strains (8, 22). In accordance with its role in virulence, PspA has been found to elicit immune responses that can protect mice
against infection with S. pneumoniae (21, 25).
Although PspA is variable in structure (12), antibodies to
PspA are highly cross-protective (25). Based on their
structure and serology, PspAs are currently divided into six clades
which make up three families (18).
The specific mechanism by which PspA confers virulence on pneumococci
is not known. However, using a bystander complement fixation assay
P. C. Aerts and H. van Dijk showed that heat-killed pneumococci
lacking PspA fixed more complement than did heat-killed pneumococci
possessing PspA (5, 7). In the current study, PspA+ and PspA Pneumococcal strains.
S. pneumoniae strains were grown
as described elsewhere (2) in Todd-Hewitt broth supplemented
with 0.5% yeast extract or on blood agar plates containing 3%
defibrinated sheep erythrocytes. Bacterial stocks were stored frozen at
Mice.
CBA/CAHN-XID/J mice (XID mice) from Jackson
Laboratories (Bar Harbor, Maine) were used in the initial experiments.
These mice carry an X-linked immunodeficiency mutation and are not able
to produce antibodies to most polysaccharides (1, 6). DBA/2J mice (C5 Infections of mice.
Pneumococci from frozen stock cultures
were thawed and plated on blood agar plates the day prior to infection
to verify the concentration of bacteria (2). On the day of
infection, separate aliquots of the same stock were diluted with
Ringer's solution to the required cell density and 2 × 105 CFU of WU2 or JY1119 was used to infect XID mice. We
used 107 CFU for intravenous infection of
complement-deficient mice, since this dose was sufficient to cause
sublethal infection in all normal littermates. Mice were injected with
pneumococci through the lateral tail vein and bled retro-orbitally with
sterile disposable micropipettes (Fisher Scientific). Whole blood was
collected serially just prior to and at various times up to 12 h
after infection. Blood (75 µl) was added to 425 µl of
phosphate-buffered saline (PBS) (0.03 M NaCl, 0.3 mM
KH2PO4, 2 mM Na2HPO4,
and 0.5 mM KCl) to prevent clotting and then placed on ice. Half the
mixture was serially diluted and used to inoculate blood agar plates
for determination of bacteremia. The remaining half of the diluted
blood sample was mixed with 250 µl of PBS containing 10 mM EDTA (pH
8.0) and centrifuged at 5,585 × g to remove
erythrocytes, and the supernatant was transferred to a fresh tube and
kept frozen at In vitro complement fixation.
Pooled blood from XID mice
with normal complement levels was allowed to clot on ice for 30 min and
then was immediately spun in a microcentrifuge to isolate the serum.
This serum was aliquoted, stored at C3 enzyme-linked immunosorbent assay.
C3 enzyme-linked
immunosorbent assay was used to monitor the disappearance of serum C3
during opsonization of bacteria in vivo. Microtiter plates were coated
overnight at 4°C with 25 µg of polyclonal goat anti-mouse C3
(Cappel) per ml diluted in 15 mM Na2CO3-30 mM
NaHCO3, pH 9.6. The next day, the antibody mixture was
removed and the plate was rinsed and blocked for 1 h with 100 µl
of 1% bovine serum albumin (Sigma) in PBS containing 10 mM EDTA, pH
7.5. Plates were subsequently washed with the same buffer containing
0.05% Tween 20. Normal mouse serum (200 ng of mouse C3/ml) and sera
collected from infected mice were diluted in washing buffer containing
0.05% bovine serum albumin and added to the wells. The plates were
then incubated at room temperature for 2 h. At the end of this
time, wells were washed and 50 µl of goat anti-mouse C3
peroxidase-conjugated antibody was added to each well. The plates were
incubated for 1 h and washed twice in wash buffer, and 100 µl of
ABTS (Sigma) substrate buffer was added. After 30 min of substrate
conversion, the plates were scanned at 405 nm with a Labsystems
Multiskan MS scanner (Scientific Consultant Inc.).
The influence of PspA on complement activation in vivo was
revealed by comparing consumption of serum C3 in XID mice after infection with WU2 (PspA+) and JY1119 (PspA
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Pneumococcal Surface Protein A Inhibits Complement
Activation by Streptococcus pneumoniae
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
chain of C3b was reduced in the presence of PspA.
We propose that PspA exerts its virulence function by interfering with
deposition of C3b onto pneumococci and/or by inhibiting formation of a
fully functional alternative pathway C3 convertase. By blocking
recruitment of the alternative pathway, PspA reduces the amount of C3b
deposited onto pneumococci, thereby reducing the effectiveness of
complement receptor-mediated pathways of clearance.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
strains of pneumococci were
used to examine the effect of PspA on bacterial virulence and
complement activation in vivo and the influence of PspA on opsonization
of pneumococci in vitro. The virulence of wild-type pneumococci and
their PspA counterparts was compared between normal and
complement-deficient mice. Our results suggest that PspA functions as
an inhibitor of factor B-mediated complement activation in vivo and as
an inhibitor of C3b deposition and/or -chain processing in vitro.
These findings are consistent with an ability of PspA to inhibit the
formation and/or function of the alternative pathway C3 convertase and
provide insights into the role of PspA in disease and the mechanism of action of protective anti-PspA antibodies.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
80°C in Todd-Hewitt broth containing 10% glycerol. The capsular
type 3 strain WU2 (PspA+) and the isogenic strain JY1119
(PspA) were used (6, 30). Derivation of the
PspA mutant has been fully described elsewhere
(30). To ensure the purity of each strain, WU2 and JY1119
were grown on blood agar plates containing gentamicin (4 µg/ml) and
erythromycin (0.3 µg/ml), respectively (2, 30).
mice) carry a spontaneous mutation in exon 7 of
the murine C5 gene which renders them deficient in serum complement C5
(28). C3-deficient mice (C3 mice) produce no
serum complement C3 due to targeted disruption of the C3 gene
(11), while factor B-deficient mice (FB mice)
produce no serum complement factor B due to targeted disruption of the
factor B gene (20). C5 mice lack the ability
to generate C5 convertases through any complement pathway and thus are
unable to produce C5a, C5b, and the cell-lytic membrane attack complex.
C3 mice lack the ability to generate C3 convertases
through the alternative pathway and do not produce the anaphylotoxin
C3a nor the opsonin C3b. They also have no serum complement lytic
activity. FB mice are unable to form the alternative
pathway C3 convertases; thus, they have no alternative complement
pathway activity and have reduced classical pathway activity
(20). C3 mice and phenotypically normal
littermates carrying one C3 allele were produced by mating
C3 mice with C57BL/6J partners and intercrossing the
F1 hybrids. The same breeding system was used to produce
FB and C5 mice and normal littermates. All
mice were 6 to 12 weeks old when used.
20°C.
80°C, and, since it contains no
antibodies against pneumococci (1, 6), used as the
complement source for in vitro opsonization. For the complement
fixation assay, freshly thawed XID mouse serum was diluted 2.5-fold in
gelatin Veronal buffer (Sigma). To five 1-ml aliquots of the diluted
serum was added 150 µl of WU2 or JY1119 (9.5 × 108
CFU) or 150 µl of sterile Veronal buffer. To determine complement fixation due to classical pathway activation, bacteria were pretreated with immunoglobulin G3 anti-type 3 capsule monoclonal antibody 16.3 for
5 min (4, 6) prior to exposure to XID mouse serum. The
mixtures were incubated at 37°C, and at various time points, a
50-µl sample was removed, diluted with an equal volume of PBS containing 10 mM EDTA, and centrifuged for 2 min at 4°C to pellet pneumococci. The supernatant was removed, and the bacterial pellet was
washed twice in PBS containing 10 mM EDTA, resuspended in 50 µl of
reducing sodium dodecyl sulfate (SDS) sample buffer, boiled for 5 min,
and loaded onto SDS-polyacrylamide gels for electrophoresis. Western
blotting was performed according to standard procedures. To monitor the
accumulation of C3 on bacteria, immunoblots were developed with
peroxidase-conjugated goat anti-mouse C3 polyclonal antibody (ICN
Pharmaceuticals, Inc.). This antibody recognizes the intact chain
(110 kDa) and 
chain (65 kDa) of mouse serum C3 and also reacts with
the various -chain fragments (~46 kDa) that remain bound to
pneumococci after C3b deposition. Protein bands were quantitated by
densitometry with the Bio-Rad gel documentation system.
RESULTS AND DISCUSSION
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
).
After intravenous infection with 105 CFU of
PspA pneumococci, clearance of bacteria was significant
within 2 h and virtually complete by 6 h (Fig.
1A). In contrast, with the PspA+ strain only marginal clearance of bacteria was
observed and the infection was fully established by 6 h (Fig. 1A).
Within 30 min after infection with the PspA strain, the
concentration of serum C3 decreased significantly and consumption of
serum C3 continued until 4 h (Fig. 1B). In contrast, there was
less activation of complement in response to the PspA+
strain. In fact, no statistically significant consumption of C3 (Fig.
1B) was measured, even in mice receiving up to 107 CFU of
PspA+ bacteria (data not shown). Beyond 6 h
postinfection, there was a net increase in serum C3 in mice infected
with either strain of pneumococci, likely due to the C3 acute-phase
response (24). These data suggest that an ability of PspA to
inhibit complement activation during the early phase of infection
allows pneumococci to evade host defense mechanisms otherwise
responsible for their clearance.
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FIG. 1.
PspA inhibits complement activation and clearance of
pneumococci. XID mice were infected intravenously with approximately
105 CFU of PspA+ or PspA
pneumococci, and blood was collected to quantitate bacteremia (A) and
serum C3 (B). The data are presented as the means ± standard
errors of the means from a total of 15 mice per group (two
experiments). Asterisks indicate significant decreases in bacteremia or
serum C3 concentrations compared to 0-h (preinfection) values
(P < 0.05, paired t test).
To investigate the point along the complement activation cascade at
which PspA exerts its influence, C3, FB,
and C5 mice and their wild-type littermates were infected
with PspA+ and with PspA pneumococci. As in
XID mice (Fig. 1A), PspA pneumococci were cleared rapidly
from the blood of wild-type mice (Fig.
2A). In stark contrast,
PspA pneumococci were not cleared by C3 or
FB mice (Fig. 2B and C). Moreover, in both
C3 and FB mice, infection with
PspA pneumococci led to bacteremia as intense as that
caused by PspA+ pneumococci. These data are in agreement
with our initial hypothesis that PspA increases virulence of
pneumococci through inhibition of complement function and suggest that
the inhibitory step targets factor B-mediated activation. In fact,
unlike deficiencies of C3 and factor B, deficiency in the late-acting
component C5 had no influence on the virulence of the
PspA strain (Fig. 2D). Thus, PspA's role in virulence
does not extend to events that require C5 cleavage or membrane attack
complex assembly. The associated mortality data, though limited,
clearly demonstrate the effectiveness of PspA as a virulence factor. Of the mice shown in Fig. 2 that were infected with the PspA+
strain, all but a single wild-type mouse died within 24 h. In contrast, for mice infected with the PspA strain no
deaths were observed in the wild-type and C5 groups, but
all C3 mice and half of the FB mice died.
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The various pathways leading to complement activation and its
proteolytic cascade that ensues have been reviewed in detail elsewhere
(26). Briefly, when complement activation is initiated the
chain of serum C3 binds covalently to the activating surface. The
covalently bound / dimer, termed C3b, composed of an and a
chain, is then recognized and bound by factor B to form C3bB. Upon
cleavage of C3b-bound factor B by the enzyme factor D, the C3
convertase C3bBb is formed. This complex is short-lived and therefore
is not an effective amplifier of the alternative pathway. However, it
is stabilized by the binding of properdin to form the alternative
pathway amplification convertase. The properdin-stabilized convertase
catalyzes the hydrolysis of additional C3 molecules, and more C3b is
deposited onto the activating surface. More C3 convertases are formed,
and the alternative pathway is amplified. Amplification is limited by
the complement regulatory enzymes factor H and factor I, which together
can cleave the chain of C3b into smaller fragments. The resulting
molecule, termed iC3b, no longer supports the amplification process,
but like C3b, it serves as a recognition molecule for complement
receptors on phagocytes.
To determine more directly if PspA increases virulence through
interference with complement-mediated opsonization of pneumococci, we
compared the amounts of C3b deposited onto PspA+ and
PspA pneumococci opsonized in vitro. Control immunoblots
of normal mouse serum revealed discrete and chains of serum C3
(110 and 65 kDa, respectively) that were absent in C3
mouse sera (Fig. 3). On serum-opsonized
pneumococci (Fig. 3, lanes 2 to 8), and chains of C3b and
variable amounts of ~46-kDa -chain fragments of iC3b were
consistently observed. Compared to PspA+ bacteria, more C3b
was deposited onto the PspA strain, as indicated by
increased levels of -chain and -chain fragments (Fig. 3, compare
lanes 4 and 5 to 7 and 8). Although treatment of pneumococci with
anticapsular antibody prior to opsonization with XID mouse serum
substantially increased C3b deposition on both the PspA+
and the PspA pneumococci (Fig. 3, compare lanes 9 to 14 with 15 to 20), again more C3b was deposited on the PspA
strain. By using the Bio-Rad gel documentation system, we compared the
relative densities of the C3b chain, chain, and -chain fragments deposited on PspA+ and PspA
pneumococci. These bands accounted for 27, 39, and 34% of the total
integrated density value for C3b on the PspA+ strain (lane
9) compared to 20, 41, and 39% on the PspA strain (lane
15), respectively. Thus, despite the overall increase in C3b deposited
onto antibody-sensitized PspA pneumococci, the relative
strength of the -chain signal is reduced by 7% compared to that on
the PspA+ strain. Although these data are limited, the
reduced contribution of the chain to the total C3b signal detected
on PspA pneumococci 2 min after exposure to serum, with
concomitant strengthening (by 5%) of the ~46-kDa -chain
fragments, does suggest that processing of C3b on PspA
pneumococci may be more rapid than on PspA+ pneumococci.
Although the precise mechanism is not yet known, these combined data
indicate that the virulence function of PspA involves inhibition of
deposition and processing of surface-bound C3b.
|
For gram-positive bacteria, opsonization with C3b and/or iC3b is an
important prerequisite for their destruction by phagocytic cells
(9, 16), and S. pneumoniae has evolved a variety
of mechanisms to avoid opsonophagocytosis. For example, on group A
streptococci, the surface M protein inhibits phagocyte complement receptor binding of deposited C3b and iC3b (27). Also, it
had been suggested earlier (29) that since C3b is fixed to
the cell wall of pneumococci, deep in the capsule, the capsule
therefore interferes with recognition of C3b by phagocytes. The
capsules of some group B streptococci contain sialic acid, which
enhances the binding of factor H to C3b, thereby preventing complement activation (13). The M protein binds factor H
(15) and another complement regulatory protein termed C4
binding protein (19), thus blocking both alternative and
classical pathway activation. Taken together, our combined in vivo and
in vitro data suggest that the mechanism by which PspA increases
virulence of pneumococci is interference with deposition of C3b and/or
prevention of formation of alternative pathway amplification C3
convertases. This process leads to an anticipated reduction in
opsonophagocytosis and explains the increased rate of clearance of
PspA bacteria from mice. The cumulative effects of PspA
on complement deposition would be expected to be greater in vivo than
in vitro since the amount of complement available and the time
available for activation are much greater. This model thus explains why PspA+ strains elicit minimal complement activation during
the early phase of infection. Circulating C3 is significantly consumed
only in mice infected with PspA bacteria. Furthermore,
although no remarkable difference in the total amount of C3b initially
bound by PspA+ and PspA pneumococci opsonized
in the absence of antibody was apparent, C3b bound to PspA+
pneumococci appears to be less readily processed during progression of
complement activation. In C3 mice, PspA
pneumococci become highly virulent, while in C5 mice
PspA bacteria are cleared from the blood as effectively
as in wild-type mice, indicating that complement activation events
proximal to C3 cleavage are targeted by PspA. In FB mice,
PspA bacteria are able to avoid clearance from the blood,
suggesting that PspA acts specifically on the alternative pathway of
complement activation. Thus, like the proposed function of M protein of
group A streptococci (3), PspA likely inhibits alternative
pathway activation. Interestingly, PspA also reduces deposition of C3b initiated by the classical pathway, as indicated by our results with
anticapsular antibody. Perhaps, PspA has an inhibitory effect on the
classical pathway C3 convertase, or it blocks recruitment of the
alternative pathway amplification loop.
In conclusion, we propose that PspA functions like the membrane
regulators of complement activation decay-accelerating factor, complement receptor type 1, and/or factors H and I, i.e., by blocking formation of or accelerating the dissociation of the alternative pathway C3 convertase. Since PspA is one of the more variable gene
products of pneumococci, understanding its precise mechanism of
pathogenesis will lead to the development of a more effective pneumococcal vaccine. The complement-inhibitory function of PspA is
probably superimposed on the capacity of certain capsules to block
phagocyte receptor access to cell wall-bound C3b, and so PspA+ pneumococci are predicted to be somewhat more
virulent than PspA pneumococci even in mice producing
anticapsular antibody. Furthermore, the serologic variation in PspA may
be an evolutionary attempt by pneumococci to avoid recognition by
antibodies that can neutralize the anticomplement function of PspA.
Recently, a protein called PspC (also known as CbpA and SpsA) has been
identified (17, 23) and shown to elicit a protective immune
response. The similarity of this molecule to PspA suggests that it
might also interfere with complement activation.
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ACKNOWLEDGMENTS |
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This work was supported by National Institutes of Health grants AI-07051, AI-21548 (D.E.B.), and AI-42183 (A.J.S.).
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0006. Phone: (205) 975-6241. Fax: (205) 934-2126. E-mail: rheu022{at}uabdpo.dpo.uab.edu.
Editor: V. A. Fischetti
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Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
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