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J Virol, August 1998, p. 6665-6670, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
T-Cell-Independent Immunoglobulin G Responses In
Vivo Are Elicited by Live-Virus Infection but Not by Immunization
with Viral Proteins or Virus-Like Particles
Eva
Szomolanyi-Tsuda,1,*
Quang P.
Le,1
Robert L.
Garcea,2 and
Raymond M.
Welsh1
Department of Pathology, University of
Massachusetts Medical Center, Worcester, Massachusetts
01655,1 and
Department of Pediatrics,
University of Colorado Health Sciences Center, Denver, Colorado
802622
Received 5 March 1998/Accepted 29 April 1998
 |
ABSTRACT |
Immunoglobulin G (IgG) responses to viruses are generally assumed
to be T-cell dependent (TD). Recently, however, polyomavirus (PyV)
infection of T-cell-deficient (T-cell receptor 
chain [TCR-] 
/ or TCR-×
/) mice was shown to elicit a protective,
T-cell-independent (TI) antiviral IgM and IgG response. A repetitive,
highly organized antigenic structure common to many TI antigens is
postulated to be important in the induction of antibody responses in
the absence of helper T cells. To test whether the repetitive structure
of viral antigens is essential and/or sufficient for the induction of
TI antibodies, we compared the abilities of three forms of PyV antigens
to induce IgM and IgG responses in T-cell-deficient mice: soluble
capsid antigens (VP1), repetitive virus-like particles (VLPs), and live
PyV. Immunization with each of the viral antigens resulted in IgM
production. VLPs and PyV elicited 10-fold-higher IgM titers than VP1,
indicating that the highly organized, repetitive antigens are more
efficient in IgM induction. Antigen-specific TI IgG responses, however,
were detected only in mice infected with live PyV, not in VP1- or
VLP-immunized mice. These results suggest that the highly organized,
repetitive nature of the viral antigens is insufficient to account for
their ability to elicit TI IgG response and that signals generated by
live-virus infection may be essential for the switch to IgG production
in the absence of T cells. Germinal centers were not observed in
T-cell-deficient PyV-infected mice, indicating that the germinal center
pathway of B-cell differentiation is TD even in the context of a virus infection.
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INTRODUCTION |
Although cognate T-cell-B-cell
cooperation is essential for T-cell-dependent (TD) humoral immunity,
antibody (immunoglobulin M [IgM] and IgG) responses to a variety of
antigens in T-cell-deficient mice (14, 15, 17, 26) indicate
that alternative, T-cell-independent (TI) mechanisms of B-cell
activation, differentiation, and isotype switching also operate in
vivo. The nature of these mechanisms and the essential characteristics
of the antigens which activate the TI pathways in vivo, however, are
not known. Many TI antigens (bacterial polysaccharides, polymerized
flagellin, etc.) have a highly organized, repetitive antigen structure,
which is thought to be essential for their ability to induce antibody
responses in the absence of T-cell help. The repeating, identical
epitopes can extensively cross-link the B-cell receptor, enabling these antigens to deliver strong activating signals to the B cells. The fact
that both in vitro and in vivo B cells respond differently to the same
antigenic epitope when it is presented in a nonrepetitive versus a
highly organized, repetitive form (2, 21) supports this
idea. It has also been suggested that there is a correlation between
the repetitive structure of certain viruses and their ability to act as
TI antigens (3, 4).
Polyomavirus (PyV) infection of 
T-cell- or and 
T-cell-deficient mice induces a TI IgM and IgG response, which provides resistance to the infection. T-cell-deficient mice survive PyV infection, whereas SCID mice have 100% acute mortality (23, 24). Thus, PyV can effectively induce TI isotype switch in vivo. In this study, PyV-infected T-cell-deficient mice were used as a model
to investigate the TI antiviral IgG responses and to analyze what role
the nature of the antigen has in TI IgM and IgG induction. Comparing
the abilities of soluble capsid proteins (VP1), repetitive virus-like
particles (VLPs), and live PyV to induce TI antibodies, we showed that
IgG responses, which require TI isotype switch, were elicited only by
infection with live virus, not by immunization with VP1 or VLPs.
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MATERIALS AND METHODS |
Mice and immunizations.
C57BL/6, CBA, and T-cell
receptor chain (TCR-) / and TCR-× / mice on a
C57BL background were obtained from the Jackson Laboratory (Bar Harbor,
Maine). Mice were immunized intraperitoneally (i.p.) with 10 µg of
purified VP1 of PyV strain RA produced by recombinant baculovirus
(20) or with the same amount of recombinant VP1 protein
assembled into VLPs in insect cultures (16). Infection with
highly purified PyV strain RA (8) was done i.p., using 7 × 105, 7 × 106, or 7 × 107 PFU/mouse; in some experiments, unpurified PyV strain
A2 was used.
VP1-specific ELISAs.
To measure PyV capsid protein-specific
antibody production in enzyme-linked immunosorbent assays (ELISAs),
96-well plates were coated with recombinant VP1 protein produced in
Escherichia coli (11) (0.03 µg/well). The serum
samples were tested in duplicate. Biotinylated horse anti-mouse IgG and
goat anti-mouse IgG and goat anti-mouse IgM plus
streptavidin-horseradish peroxidase (HRP) (Vector Laboratories Inc.,
Burlingame, Calif.) were used to measure IgM and IgG, respectively. To
detect IgG isotypes a Southern Biotech (Birmingham, Ala.) isotyping kit
and HRP-labeled rat anti-mouse IgG2a from Pharmingen (San Diego,
Calif.) were used. 3,3',5,5'-Tetramethyl-benzidine tablets (Sigma, St.
Louis, Mo.) were used as the substrate to develop the enzyme reaction.
Plates were read at an optical density of 450 nm (OD450) by
a THERMOMAX plate reader and SoftMax 2.3 software
(Molecular Devices Corp., Menlo Park, Calif.). The VP1 specificity of
the ELISAs was tested with wells coated with proteins (0.03 µg/well)
derived from an E. coli lysate purified the same way as the
recombinant VP1 protein. None of the serum samples tested gave OD
readings above the background with this control antigen.
GC staining.
Frozen, OCT-embedded spleen sections were fixed
and stained with HRP-peanut agglutinin (PNA) (Vector Laboratories) to
visualize germinal centers (GC) and counterstained with hematoxylin.
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RESULTS |
Magnitude and isotype profile of TI IgG response to PyV in
T-cell-deficient mice.
The magnitude of virus-specific TI IgG
production in PyV-infected TCR- / and TCR-× / mice
was evaluated by measuring PyV major capsid protein (VP1)-specific IgG
endpoint titers in ELISAs. On day 14 following i.p. infection with
7 × 106 PFU of purified PyV strain RA, TCR- /
and TCR-× / mice had VP1-specific serum IgG titers of
1.6 × 104, which was 1 log lower than the IgG values
detected in wild-type C57BL/6 mice (1.6 × 105) (Fig.
1A and B). With another PyV strain, A2,
the virus-specific IgG levels in T-cell-deficient mice were also
~10% of those measured in serum samples of immunocompetent mice
(Fig. 1C). Analysis of the isotype distribution of the virus-specific
IgG indicated that all four IgG subclasses were induced by PyV
infection in wild-type C57BL/6 mice, with IgG2a and IgG2b being
predominant. In TCR-× / mice, no measurable VP1-specific
IgG1 was observed, suggesting a T-cell dependence for the generation of
this isotype (Fig. 2). In these
T-cell-deficient mice with a C57BL/6 background, IgG2b was the
predominant virus-specific IgG subclass, and various amounts of IgG2a
and IgG3 were also consistently detected. Interestingly, TCR- /
and TCR-× / mice with 129 × C57BL background produced predominantly IgG2a in response to PyV infection (data not shown). TCR- / and TCR-× / mice did not show reproducible
differences in the magnitude of VP1-specific IgG production, suggesting
that T cells do not significantly influence TI antibody
responses to PyV (Fig. 1C and 3).
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FIG. 1.
Magnitude of IgG response to PyV in immunocompetent and
T-cell-deficient mice. Shown are PyV VP1-specific serum IgG titers on
day 14 postinfection. In experiments 1 and 2, the IgG titers of pooled
serum samples (n = 3) from C57BL/6, CBA, TCR- /,
and TCR-× / mice infected i.p. with 7 × 106 PFU of purified PyV strain RA were determined by
VP1-specific ELISAs and expressed as the reciprocal log10
endpoint dilutions giving absorbance values at 450 nm above the
background. Experiment 3 shows data obtained with mice infected with
another PyV strain, A2. Pooled blood samples from C57BL/6 and TCR-
/ mice (n = 6) and three individual samples from
TCR-× / mice were tested.
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FIG. 2.
Isotype distribution of VP1-specific IgG in
immunocompetent and T-cell-deficient PyV-infected mice. VP1 antigen-
and isotype-specific ELISAs were performed with pooled sera from
C57BL/6 (n = 5) and TCR-× /
(n = 5) mice in 1:50 dilution. The serum samples were
taken on day 21 following i.p. infection with PyV strain A2. The
absorbance values of serum samples from uninfected mice were 0.048 to
0.06.
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FIG. 3.
VP1-specific IgG response to VLPs and PyV in TCR-
/ and TCR-× / mice. Serum samples obtained on day 14 following immunization with 70 HAU of VLPs or 70 HAU of PyV were
assayed in 1:100 serum dilution. The absorbance (OD450)
values are means and standard deviations (n = 3 for
VLP-immunized TCR- / and TCR-× / mice and
PyV-infected TCR- / mice; n = 2 for PyV-infected
TCR-× / mice). The horizontal line indicates the background
absorbance obtained with uninfected mouse serum.
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TI IgM responses to viral capsomeres, VLPs, and PyV.
PyV is a
nonenveloped icosahedral DNA virus. The major capsid protein, VP1,
forms pentameric capsomers, and 72 capsomeres form the viral capsid
(22). Because several known TI antigens have a highly
organized, repetitive antigenic structure, it has been hypothesized
that the structural repetitiveness is an essential characteristic which
enables viruses to act as TI antigens (3, 4). The repetitive
structure may function by cross-linking the B-cell receptors, thus
providing signals activating antibody production.
To test whether the repetitive structure of PyV capsid is essential
and/or sufficient for the induction of TI IgM and IgG
antibody
responses in vivo, three forms of the PyV VP1 antigen
were used to
immunize T-cell-deficient mice. Purified pentameric
VP1 capsomeres were
used as soluble protein antigens (
11,
20).
These capsomeres
may randomly associate (
19) but do not form
highly organized
structures. The source of highly organized, repetitive
viral antigens
were VLPs, which are empty viral capsids assembled
in insect cell
cultures after expression of the VP1 protein by
using a recombinant
baculovirus vector (
16). The VLPs used in
the experiments
were morphologically intact judged by electron
microscopy. Purified PyV
virions were used as live viral antigens
(
8). The amount of
protein antigens (VP1 and VLP) used in these
studies was 10 µg/mouse
i.p., an antigen dose equivalent to 70
hemagglutination units (HAU) or
7 × 10
7 PFU of PyV. Live-virus infections were
performed with highly
purified PyV strain RA given i.p. in three
different doses: 70,
7, and 0.7 HAU, corresponding to ~7 × 10
7, 7 × 10
6, and 7 × 10
5 PFU, respectively. VP1-specific IgM and IgG responses
to the
three forms of antigens were determined.
The VP1-specific IgM response peaked on day 4 in both wild-type C57BL/6
and TCR-
×
/
mice (Fig.
4A). On
day 4, VP1-immunized
immunocompetent and T-cell-deficient mice both had
a low but measurable
level of VP1-specific IgM. Both strains of mice,
however, secreted
significantly (10-fold) higher levels of IgM in
response to the
repetitive antigen, VLP (Fig.
4B and C). Infection with
live,
replicating PyV (7 × 10
6 and 7 × 10
5 PFU) led to two- to eightfold further increases in peak
virus-specific
IgM levels compared to that for VLP immunization. These
results
show that the IgM responses induced by viral proteins or live
virus in the absence of T cells are similar in magnitude to the
IgM
production observed in immunocompetent mice, suggesting that
the early
IgM response is TI even in wild-type mice. The data
also support the
hypothesis that structural repetitiveness enhances
the efficiency of TI
IgM induction (
3,
4), consistent with
similar findings for
mice immunized with different forms of the
vesicular stomatitis virus
glycoprotein (
1,
2,
7).
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FIG. 4.
Virus-specific IgM production in immunocompetent and
T-cell-deficient mice in response to viral capsid proteins, VLPs, and
live virus. (A) Time course of VP1-specific IgM response. To compare
the IgM levels in serum samples obtained at different time points and
assayed separately, the absorbance values were converted to relative
units. Absorbance of a positive control serum (pooled serum from day 14 PyV-infected C57BL/6 mice, which was included in every assay) was used
as reference and considered 100 U. Data obtained with serum samples
(1:100 dilutions) from a C57BL/6 mouse ( ) and a TCR-× /
mouse ( ) injected with 7 × 106 PFU of PyV
(equivalent to 7 HAU) strain RA and two TCR-× / mice ( ,
 ) infected with 7 × 105 PFU of PyV (0.7 HAU)
strain RA are shown. (B) VP1-specific IgM titers on day 4 following
immunization expressed as reciprocal log10 of the endpoint
dilutions giving positive values in ELISAs. The data shown were
obtained from pooled sera from C57BL/6 mice immunized with 70 HAU of
VP1 (n = 2), 70 HAU of VLPs (n = 3), or
7 HAU of PyV (n = 1); TCR- / mice injected with
70 HAU of VP1 (n = 2) or 70 HAU of VLPs
(n = 3); and TCR-× / mice injected with 0.7 HAU of PyV (PyVlow; n = 3) or 7 HAU of PyV
(n = 1). KO, knockout. (C) VP1-specific IgM in 1:100
dilutions of sera obtained on day 7 following immunization of
T-cell-deficient mice. The OD450 values are means and
standard deviations for C57BL/6 mice immunized with 70 HAU of VP1
(n = 2), 70 HAU of VLPs) (n = 3), or 7 HAU of PyV (n = 1); TCR- / mice injected with 70 HAU of VP1 (n = 2) or 70 HAU of VLPs (n = 3); and TCR-× / mice injected with 0.7 HAU of PyV
(PyVlow, n = 3) or 7 HAU of PyV
(n = 1).
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TI IgG responses are elicited by virus infection but not by
immunization with viral capsomeres or VLPs.
IgG responses to PyV
were detected from day 7 in PyV-infected C57BL/6 and TCR-× /
mice, and the VP1-specific IgG levels progressively increased until day
21, when the experiment was terminated (Fig.
5). In the absence of T cells ( or
and ), neither the VP1 capsomeres nor the VLPs induced IgG
production in T-cell-deficient mice (Fig. 5 and
6). In experiment 1, on day 14 postinfection the VP1-specific IgG endpoint titers were 104
in both TCR- / and TCR-× / PyV-infected mice.
T-cell-deficient mice immunized with viral proteins did not have
detectable IgG above 1:100 serum dilution (Fig. 6). In experiment 2, on
day 21 after administration of antigens in wild-type C57BL/6 mice, both capsomeres and VLPs induced IgG responses with 3.2 × 103 and 1.2 × 104 endpoint titers,
respectively. PyV-infected C57BL/6 mice had an IgG titer of 8 × 105 on day 21, whereas TCR-× / mice had a titer
of 4 × 104, consistent with findings shown previously
(Fig. 1 and 6). No VP1-specific IgG was detected, however, in
T-cell-deficient mice immunized with VP1 proteins or VLPs (Fig. 6).
These results strongly suggest that the highly organized repetitive
antigen structure, which VLPs possess similarly to live virus, is not
sufficient for the induction of a TI IgG response. We conclude that
other signals generated in the context of live virus infection may be required for a TI isotype switch.
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FIG. 5.
Time course of VP1-specific IgG production in
immunocompetent and T-cell-deficient mice in response to VP1, VLPs, and
PyV. The IgG response, expressed in relative units, was calculated as
described in the legend to Fig. 4. Each curve represents data obtained
by sequential bleeding of a mouse immunized with 7 HAU of PyV (),
0.7 HAU of PyV (), 70 HAU of VLPs (), or 70 HAU of VP1 ().
KO, knockout.
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FIG. 6.
VP1-specific IgG titers on days 14 and 21 following
immunization. The IgG titers are expressed as log10 of
reciprocal endpoint dilutions giving positive values in ELISAs. In
experiment 1, mean values and standard deviations for groups of mice
(three per group) immunized with 70 HAU of VP1, 70 HAU of VLPs, or 7 HAU of PyV are shown. In experiment 2, pooled sera from C57BL/6 mice
immunized with 70 HAU of VP1 (n = 2), 70 HAU of VLPs
(n = 3), or 7 HAU of PyV (n = 1),
TCR- / mice injected with 70 HAU of VP1 (n = 2)
or 70 HAU of VLPs (n = 3), and TCR-× / mice
injected with 0.7 HAU of PyV (PyVlow; n = 3) or 7 HAU of PyV (n = 1) were tested. KO, knockout.
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Simultaneous infection of VLP-immunized TCR-
×
/
mice with
lymphocytic choriomeningitis virus (LCMV) did not result in
inducing
VP1-specific IgG production. Serum samples from all four
mice on day 14 following infection with 5 × 10
4 PFU of LCMV and
immunization with 70 HAU of VLPs i.p. had VP1-specific
IgG levels below
the background of detection in 1:100 dilution.
Because LCMV infection
can itself elicit antiviral TI IgG responses
(
5), this
result suggests that systemic elevation of cytokines
or activation of
certain cell types induced by the virus infections
is not sufficient to
help the efficient TI isotype switch and
argues for the importance of
local signals.
Lack of GC formation in PyV-infected T-cell-deficient mice.
In
the course of a primary antibody response to TD antigens, B cells
follow one of two distinct pathways of differentiation. They
differentiated into antibody-secreting plasma cells, or they migrate to
the GC, where B cells proliferate, undergo affinity maturation, and
enter the B-cell memory pool (9, 12, 25). T-cell-B-cell
interactions were shown to be essential for the GC induction in mice
immunized with protein antigens (6, 10), and classical TI
antigens typically do not induce GC development (17).
To test whether the GC pathway of B-cell differentiation requires
T-cell-derived signals in the course of a virus infection,
we tested GC
formation in PyV-infected T-cell-deficient mice.
GC B cells express a
surface receptor for the lectin PNA, and
this allows for the
identification of GC (
25). Frozen sections
of spleens from
day 14 PyV-infected TCR-
/
and TCR-
×
/
as well as
from C57BL/6 mice were analyzed for the presence of
GC by
immunohistochemistry. The formation of typical GC was not
detectable in
TCR-
/
(Fig.
7B) and TCR-
/
(data not shown)
mice, although small groups of weakly
PNA-staining cells were
seen in a fraction of the animals. The spleen
sections from C57BL/6
mice exhibited numerous strongly PNA-staining
areas characteristic
of GC formation (Fig.
7A). These results suggest
that the development
of GC is TD even in the context of a virus
infection.
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FIG. 7.
Lack of GC formation in PyV-infected TCR- / and
TCR-× / mice. Frozen sections of spleens were stained with
HRP-PNA (brown) and counterstained with hematoxylin (blue). (A) Spleen
of a C57BL/6 mouse on day 12 postinfection. The PNA-staining areas
indicate the presence of GC. (B) Spleen of a TCR- / mouse on day
12 postinfection.
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DISCUSSION |
This study demonstrates that virus infection can elicit not only
IgM but also IgG responses without T-cell help, whereas IgG production
depends on T-cell help when the mice are immunized with viral proteins.
Repetitive antigens that strongly cross-link B-cell receptors
(bacterial polysaccharides, haptenated polymers, and viruses) induce
B-cell responses in the absence of T-cell help. It has been postulated
that the highly structured organization of the epitope has a major role
in the induction of TI antibodies. Our results indicate that the highly
organized repetitive antigen structure of viruses indeed increases the
efficiency of TI IgM responses but is not sufficient to induce
antigen-specific IgG production. Therefore, we hypothesize that for TI
switch to IgG, B cells require signals generated by live-virus
infection.
Two observations suggest the importance of local signals in the
immediate vicinity of the responding B cell: (i) the magnitude of TI
IgG responses did not change with changing the infecting virus dose
(from 7 × 105 to 7 × 107 PFU); and
(ii) administration of VLP and a heterogeneous live virus did not
result in a bystander induction of IgG response to the VLPs, indicating
that systemic elevation of cytokines or activation of certain cell
types is not the mechanism resulting in efficient isotype switch. Based
on these findings, we suggest that the very high local antigen
concentrations reached during infection with live, replicating virus,
which may be present at high levels for a prolonged time, may
contribute to the efficient induction of TI responses. Another factor
may be the local inflammatory response accompanying virus infection,
which results in the activation of NK cells, macrophages, and dendritic
cells and the induction of a variety of cytokines. In this model, the
infectious nature of the antigen would be indicated by the structure
and the high local concentration, together with signals from the innate
immune system, and the sum of these signals would trigger B-cell
differentiation and isotype switch as well as IgM and IgG production
even in the absence of T-cell help. These mechanisms would allow the
generation of protective immunity against microbial pathogens even in
an organism with impaired T-cell functions but would still safeguard against autoimmunity.
The antiviral IgG isotypes produced in PyV-infected TCR- / and
TCR-× / mice were predominantly IgG2b, with various amounts
of IgG2a and IgG3 also synthesized. No virus-specific IgG1 was detected
in these mice, however, suggesting that the synthesis of IgG1 depends
on T-cell help. This finding is consistent with a report
describing antiviral IgG2a, IgG2b, and IgG3 responses, but no IgG1
production, in LCMV-infected CD40L / mice, which are deficient in a
crucial component of T-cell help (27).
Isotype switching occurs in the periarteriolar lymphoid sheaths
and in the GC. GC are also the sites associated with affinity maturation and B-cell memory development (9). The lack of
typical GC in the spleen of PyV-infected T-cell-deficient mice suggest that the GC pathway of B-cell differentiation is TD even in the context
of a virus infection. Affinity maturation may not be absolutely dependent on the presence of GC, however, since in
lymphotoxin--deficient mice, which fail to develop GC, affinity
maturation of the antibody response following immunization with a very
high antigen dose was found (13). It will be interesting
therefore to test whether affinity maturation occurs in virus-infected
T-cell-deficient mice.
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ACKNOWLEDGMENTS |
We thank David Parker and Philippa Marrack for critical
comments on the manuscript; we thank Jie Yin and Yu Liu for technical assistance.
This research was supported by Public Health Service grants CA 66644 (to E.S.-T.), CA 37667 (to R.L.G.), and CA 34461 (to R.M.W.) from the
National Cancer Institute.
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FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pathology, University of Massachusetts Medical Center, 55 Lake Ave.
North, Worcester, MA 01655. Phone: (508) 856-3039. Fax: (508) 856-5780. E-mail: Eva.Szomolanyi-Tsuda{at}banyan.ummed.edu.
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J Virol, August 1998, p. 6665-6670, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
