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Infection and Immunity, July 2000, p. 4274-4281, Vol. 68, No. 7
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Influence of 
2-Integrin Adhesion Molecule
Expression and Pulmonary Infection with Pasteurella
haemolytica on Cytokine Gene Expression in Cattle
Haa-Yung
Lee,1,
Marcus E.
Kehrli Jr.,1,
Kim
A.
Brogden,2
Jack M.
Gallup,3 and
Mark R.
Ackermann3,*
Metabolic Disease and Immunology Research
Unit1 and Respiratory and Neurologic
Disease Research Unit,2 National Animal
Disease Center, Agricultural Research Service, U.S. Department of
Agriculture, Ames, Iowa 50010, and Department of Veterinary
Pathology, College of Veterinary Medicine, Iowa State University,
Ames, Iowa 50011-12503
Received 7 October 1999/Returned for modification 29 October
1999/Accepted 12 April 2000
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ABSTRACT |
2-Integrins are leukocyte adhesion molecules
composed of alpha (CD11a, -b, -c, or -d) and beta (CD18) subunit
heterodimers. Genetic CD18 deficiency results in impaired neutrophil
egress into tissues that varies between conducting airways and alveoli of the lung. In this study, we investigated whether CD18 deficiency in
cattle affects proinflammatory cytokine (PIC) expression in pulmonary
tissue after respiratory infection with Pasteurella haemolytica. Cattle were infected with P. haemolytica
via fiberoptic deposition of organisms into the posterior part of the
right cranial lung lobe. Animals were euthanized at 2 or 4 h
postinoculation (p.i.), and tissues were collected to assess PIC gene
expression using antisense RNA probes specific for bovine
interleukin-1
(IL-1), IL-1, IL-6, gamma interferon (IFN-
),
and tumor necrosis factor alpha (TNF-) along with the -actin
(-Act) housekeeping gene. Expression of PIC was induced at 2 h
p.i. in P. haemolytica-infected cattle and continued to
4 h p.i. At 2 h p.i., induction of gene expression and
increase of cells that expressed PIC were observed both in
CD18+ and CD18
cattle after inoculation of
P. haemolytica. The induction of gene expression with
P. haemolytica inoculation was more prominent in
CD18 cattle than in CD18+ cattle by
comparison to pyrogen-free saline (PFS)-inoculated control animals. At
4 h p.i., however, the induction of PIC, especially IL-1, IL-6,
and IFN-, in the lungs of CD18+ cattle inoculated with
P. haemolytica was greater than that in lungs of the
CD18 cattle. IFN- and TNF- genes were not increased
in P. haemolytica-inoculated CD18 cattle
lungs compared to the PFS-inoculated control lungs at 4 h p.i. In
PFS-inoculated lungs, we generally observed a higher percentage of
cells and higher level of gene expression in the lungs of
CD18 cattle than in the lungs of CD18+
cattle, especially at 4 h p.i. The rate of neutrophil infiltration into the lungs of CD18 cattle at 2 h p.i. was
significantly higher than that of CD18+ cattle; at 4 h
p.i., there was no difference between the two groups. These data
suggest that 2-integrins may contribute to the induction
of expression of some PIC genes, as a consequence of P. haemolytica infection.
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INTRODUCTION |
Biotype A serotype 1 Pasteurella haemolytica is the primary bacterium responsible
for shipping fever, or bovine pneumonic pasteurellosis (34),
a disease characterized by acute lobar fibrinonecrotizing pneumonia
(34, 49, 50). Several virulence factors of P. haemolytica have been identified (15).
Lipopolysaccharide (LPS) and leukotoxin are the best-known stimulators
of inflammation in bovine pneumonic pasteurellosis (11, 13, 15,
42, 46, 47, 49, 50). These virulence factors stimulate a variety of respiratory tract cells such as alveolar and intravascular macrophages, mast cells, and endothelial cells, and these cells express
and produce inflammatory mediators. The inflammatory mediators secreted
by respiratory tract cells are proinflammatory cytokines (PICs) such as
interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha (TNF-),
complement components, hydrolytic enzymes, and chemokines (20, 28,
33, 38, 40, 41, 48). Once secreted, these inflammatory mediators
trigger an inflammatory cascade. Neutrophils are known to be the
primary infiltrating inflammatory cells involved in clearing infections
in the lungs; however, prolonged activation of neutrophils may induce
severe tissue damage by the production of oxygen-derived free radicals
and enzymes such as elastase (9, 10, 17, 27, 45).
Furthermore, these inflammatory mediators induce expression of adhesion
molecules on leukocytes and endothelial cells that facilitate the
infiltration of additional leukocytes into inflamed tissues (6, 9,
10, 27, 45).
Bovine leukocyte adhesion deficiency (BLAD) is an autosomal recessive
genetic disease resulting from one amino acid substitution (D128G) in
the subunit (CD18) of the 2-integrin (CD11/CD18) superfamily (LFA-1, Mac-1, p150, 95) (23-25, 32, 35, 39). This 2-integrin mediates tight adhesion of leukocytes
onto endothelial membrane of inflamed tissue (3). Leukocytes
from BLAD-affected animals express no functional CD18 (3).
The affected animals (referred to as BLAD or CD18) suffer
recurrent bacterial, viral, or fungal infections (5, 23-25, 30,
31). CD18 cattle often die because of respiratory
or enteric infections despite antibiotic therapy (4).
Another prominent characteristic of BLAD is progressive neutrophilia
due to impaired transmigration of neutrophils across the vascular
endothelium into sites of infection (2, 4, 19). In pneumonic
lungs of CD18 cattle, however, remarkable levels of
neutrophil infiltration were observed in the alveolar lumina (2,
4). Binding of 2-integrin with LPS or the counter
receptor, intercellular adhesion molecule, activates resting leukocytes
(8, 19, 22, 29). In this study, we compared PIC gene
expression in lungs of CD18+ and CD18 cattle
at 2 and 4 h after inoculation with P. haemolytica. In situ hybridization was used to measure PIC gene expression.
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MATERIALS AND METHODS |
Animals and P. haemolytica inoculation.
Twelve
Holstein cattle were used for this experiment. Half of them were
confirmed CD18 homozygous, and the other half were
age-matched normal CD18+ cattle (23-25, 35,
39). Both CD18 (BLAD) and CD18+
(normal) cattle were inoculated with 8 ml of 107 CFU of
P. haemolytica per ml in pyrogen-free saline (PFS)
followed by 10 ml of sterile PFS by fiberoptic bronchoscopy into the
right cranial lung lobe as described previously (12). The
left lobe of the lung, inoculated with 18 ml of sterile PFS, served as
saline-treated control. Animals were euthanized at 2 and 4 h after
inoculation with P. haemolytica. Lung tissues were collected
at necropsy and fixed in neutral buffered 10% zinc formalin for
histological preparation.
Probe synthesis for in situ hybridization.
Bovine
sequence-specific RNA probes for five different PICs, IL-1, IL-1,
IL-6, gamma interferon- (IFN-), and TNF-, and the -actin
(-Act) housekeeping gene were synthesized. Briefly, cDNA was reverse
transcribed from bovine leukocyte total RNA using random hexameric
primers and subjected to PCR amplification using probe-specific primer
pairs (Table 1).
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TABLE 1.
Sequences of oligomers used for PCR amplification of
bovine cytokine-specific cDNA fragments used for synthesis
of riboprobesa
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The linear plasmid DNA was transcribed in vitro using either T7 or SP6
RNA polymerase with ATP, CTP, GTP, and digoxigenin-labeled
UTP
(Boehringer Mannheim, Indianapolis, Ind.) as a labeling agent
for
antisense- or sense-strand probe, respectively. The antisense-strand
probe was used for detection of gene expression because it hybridizes
with mRNA by forming a complementary double strand. The sense
strand
probe was used as a negative control to assess nonspecific
binding.
In situ hybridization.
Paraffin-embedded tissue sections
were deparaffinized and treated with proteinase K (10 µg/ml;
Boehringer Mannheim) for 30 min at 37°C. Slides were washed with
diethyl pyrocarbonate (Sigma, St. Louis, Mo.)-treated
phosphate-buffered saline and then dried. Fifty microliters of RNA
probe (0.5 mg of RNA/ml) in hybridization solution (50% formamide,
25% diethyl pyrocarbonate-treated H2O, 3× SSC [1× SSC
is 0.15 M NaCl plus 0.015 M sodium citrate], 1× Denhardt's solution,
0.2 mg of yeast tRNA per ml, 50 mM sodium phosphate [pH 7.4], 10%
dextran sulfate) was applied onto a sample slide and covered with a
coverslip. Slides were heated at 90°C for 10 min and were hybridized
16 h in a humidified chamber at 60°C. To remove unbound probe,
slides were incubated for 30 min at 37°C with RNase A (20 mg/ml;
Boehringer Mannheim), washed sequentially in 2× SSC for 5 min, 1× SSC
for 5 min, and 0.5× SSC for 1 h at 60°C, and finally washed
with 0.5× SSC for 5 min at room temperature. Slides were then
incubated with sheep antidigoxigenin antibody labeled with alkaline
phosphatase and developed in
5-bromo-4-chloro-3-indolylphosphate-nitroblue tetrazolium (NBT-BCIP;
Boehringer Mannheim) solution in the dark for 18 h. After
chromogen development, slides were counterstained with nuclear fast red
for 3 min and coverslipped with aqueous mounting medium (Accurate
Chemical & Scientific Corp., Westbury, N.Y.) (7).
Macrophage staining.
Monoclonal antibody EBM11 (anti-CD68;
DAKO, Carpenteria, Calif.) was used for detection of macrophages in
lung tissues (1). Briefly, sections of lung tissues were
deparaffinized and treated with 0.25% bacterial protease (type XIV;
Sigma) in Tris buffer (pH 7.6) for 30 min at 37°C. The primary
antibody, monoclonal mouse anti-CD68, was diluted 1:25 and applied and
incubated overnight at 4°C. Peroxidase-labeled goat anti-mouse
immunoglobulin G (IgG) was used as the secondary antibody with
3',3-diaminobenzidine substrate (Vectastain ABC kit; Vector
Laboratories, Burlingame, Calif.). Slides were counterstained with hematoxylin.
Neutrophil staining.
For neutrophil staining, lead
thiocyanate [Pb(II) SCN; Aldrich, Milwaukee, Wis.] was used for
antigen retrieval (unpublished data). Deparaffinized tissues were
treated in boiling Pb(II) SCN (1%) for 1.5 min and then remained in
the same solution additional 10 min with the heat turned off (beaker
still on heating block). Slides were allowed to cool for 15 min at room
temperature in the saturated Pb(II) SCN solution under a hood.
Endogenous peroxidase blocking was performed for 20 min at room
temperature. The sections were treated with 10% normal goat serum for
15 min and labeled with a 1:150 dilution of secondary antibody
(anti-mouse IgG [Fab-specific] biotin conjugated; Sigma) for 1 h
at room temperature. The sections were incubated with
streptavidin-horseradish peroxidase (Kirkegaard & Perry Laboratories,
Gaithersburg, Md.) for 30 min and subjected to a color reaction with
diaminobenzidine (Kirkegaard & Perry Laboratories) for 15 min. After 15 min of incubation, the sections were counterstained with hematoxylin
for 1 min and coverslipped.
Data analysis.
Two scoring system were applied to five
independent fields on each slide. The first assessment was to evaluate
the level of gene expression on a per-cell basis. Subjective scoring of
signal intensity was scaled according to the color reaction: 0, no
chromogen staining; 1, pale blue; 2, blue to purple; 3, dark purple.
Another criterion for the scoring system was the percentage of positive cells identified in the first evaluation. Subjective scoring of positive cells was as follows: 0, no positive cells; 1, 1 to 30% of
cells positive; 2, 30 to 70% of cells positive; 3, >70% of cells
positive. The mean of each slide was calculated from five independent
observations in a given sample. The mean of each group was an average
of individual tissue means, with standard error of mean.
The data were examined using the Kruskal-Wallis one-way analysis of
variance by ranks to evaluate the effects of CD18 and
P. haemolytica inoculation for the expression of the PIC
genes.
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RESULTS |
Various levels of cytokine gene expression were detected by
cytokine-specific RNA probes (Fig. 1).
Inoculation of P. haemolytica induced PIC gene expression
and increased numbers of cells expressing PIC genes in lungs of both
CD18+ and CD18 cattle at both 2 and 4 h
postinoculation (p.i.) compared to PFS-inoculated lungs (Fig. 2 to 5).
The induction of IL-1, IL-6, and TNF- gene expression at 2 h
after inoculation with P. haemolytica was statistically significant in CD18 cattle (P < 0.05),
and only IL-6 was induced significantly in CD18+ cattle
compared to PFS-inoculated animals (Fig.
2). The induced level of PIC gene
expression between P. haemolytica-inoculated CD18+ and CD18 cattle, however, was not
statistically different (Fig. 2). The number of cells that expressed
PIC except IFN- also increased substantially at 2 h after
inoculation with P. haemolytica in lungs of both
CD18+ and CD18 animals (Fig.
3). From 2 to 4 h p.i., expression
of some cytokines especially IL-1 and IFN-, increased
progressively in CD18+ cattle treated with P. haemolytica, but no significant increase was observed in
CD18 animals (Fig. 2 and
4). Proinflammatory cytokine expression
by cells in both CD18+ and CD18 animals also
increased 4 h after inoculation with P. haemolytica, but the increase was not statistically significant compared to PFS-inoculated animals (Fig. 4). The same result was observed in the
increase of cell numbers that expressed PIC genes at 4 h after
inoculation with P. haemolytica (Fig.
5). In the PFS-inoculated lungs,
CD18 cattle had a tendency (that was not statistically
significant) to express higher levels of PIC genes and had more cells
expressing PIC genes than CD18+ cattle, especially in
4-h-p.i. groups (Fig. 4 and 5).
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FIG. 1.
Photomicrographs of bovine lung tissues in which IL-1
or IFN- mRNA is detected by in situ hybridization. Hybridized cells
were stained with alkaline phosphatase and NBT-BCIP substrate
(magnification, ×100). 1, CD18+ animal inoculated with PFS
and examined for IFN-; 2, CD18 animal inoculated with
P. haemolytica and examined for IFN-; 3, CD18+ animal inoculated with PFS and examined for IL-1;
4, CD18 animal inoculated with P. haemolytica
and examined for IL-1.
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FIG. 2.
Differences of proinflammatory cytokine gene expression
in pulmonary tissues from P. haemolytica-infected (P. hae) and noninfected (Sal) lobes in CD18+ and
CD18 cattle 2 h p.i. Level of cytokine gene
expression means the intensity of staining per cell. Subjective scoring
was applied according to the color reaction: 0, no signal; 1, low
expression; 2, moderate expression; 3, high expression. The scores
represent the average of an individual tissue within a group with
standard error of mean (n = 3). The data were examined
using the Kruskal-Wallis one-way analysis of variance by ranks to
evaluate the effects of CD18 and P. haemolytica inoculation
on expression of the PIC genes. The asterisk indicates a statistically
significant difference (P < 0.05) between P. haemolytica- and PFS-inoculated lungs within a genetic group for
expression of a given cytokine.
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FIG. 3.
Amount of cells that expressed proinflammatory
cytokine gene in pulmonary tissues from P. haemolytica-infected (P. hae) and noninfected (Sal)
lobes in CD18+ and CD18 cattle 2 h p.i.
Values for cytokine expression-positive cells are estimates of the
percentage of cells that hybridized with a given cytokine RNA probe.
Most stained cells were macrophages and neutrophils. Subjective scoring
was used for estimation of positive cells: 0, no positive cells; 1, <30% of positive cells among total cells; 2, 30 to 70% positive
cells among total cells; 3, >70% positive cells among total cells.
Scores represent the average for each tissue within a group, with
standard error of the mean (n = 3). The data were
examined using the Kruskal-Wallis one-way analysis of variance by ranks
to evaluate the effects of CD18 and P. haemolytica
inoculation on expression of the PIC genes. The asterisk indicates a
statistically significant difference (P < 0.05)
between P. haemolytica- and PFS-inoculated lungs within a
genetic group for expression of a given cytokine.
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FIG. 4.
Differences of proinflammatory cytokine gene
expression in pulmonary tissues from P. haemolytica-infected
(P. hae) and noninfected (Sal) lobes in CD18+
and CD18 cattle 4 h p.i. For details, see the legend
to Fig. 2.
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FIG. 5.
Amount of cells that expressed proinflammatory cytokine
genes in pulmonary tissues from P. haemolytica-infected
(P. hae) and noninfected (Sal) lobes in CD18+
and CD18 cattle 4 h p.i. For details, see the legend
to Fig. 3.
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Inoculation with P. haemolytica increased infiltration of
circulating leukocytes. Increased numbers of neutrophils and
macrophages in P. haemolytica-inoculated lungs were observed
(Fig. 6 and Table 2). Neutrophils were more prominent than
macrophages in P. haemolytica-inoculated bovine lungs at
both 2 and 4 h p.i. (Table 2). The increase of neutrophils in
lungs of CD18 animals was statistically significant both
2 and 4 h after inoculation with P. haemolytica but at
only 4 h p.i. in CD18+ animals; the increase in
macrophages was not statistically significant (Table 2).
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FIG. 6.
Photomicrographs of bovine lung tissue stained with
either monoclonal mouse anti-CD68 for macrophages or goat anti-mouse
IgG (Fab specific) for neutrophils (magnification, ×250). 1, CD18 animal inoculated with PFS and examined for
neutrophils; 2, CD18 animal inoculated with P. haemolytica and examined for neutrophils; 3, CD18
animal inoculated with PFS and examined for macrophages; 4, CD18 animal inoculated with P. haemolytica and
examined for macrophages.
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TABLE 2.
Percentage of labeled neutrophils and macrophages in
lungs of CD18+ and CD18 cattle 2 or 4 h
after inoculation with PFS or P. haemolytica
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DISCUSSION |
Basal PIC gene expression in PFS-inoculated lung tissues of
CD18 cattle is generally higher than in healthy
CD18+ cattle, possibly the result of chronic activation of
CD18 animals' immune system due to recurrent and/or
chronic infection (23-25, 30, 31). Kehrli et al. reported
selected functional abnormalities of neutrophils in CD18
cattle (23, 24, 31). They observed diminished levels
of phagocytosis, ingestion and associated reactive oxygen generation, myeloperoxidase-dependent iodination, and extracellular release of
elastase by neutrophils from CD18 animals (23,
24, 31). All of these dysfunctions of CD18
neutrophils are related to the lack of functional activities of
complement receptors (CR3 and CR4) that are part of
2-integrin functions.
The function of integrin is not restricted to mediating cell-to-cell
adherence and migration of immune cells but also involves signal
transduction (17, 18, 36, 37, 43). Expression of PIC genes
increased in tissues of both CD18+ and CD18
cattle following inoculation with P. haemolytica. At 2 h p.i., the augmentations of PIC gene expression and of percentages of PIC gene-expressing cells with P. haemolytica inoculation
were almost the same between CD18+ and CD18
cattle. At 4 h p.i., however, the lung tissue of CD18+
cattle expressed higher levels of IL-1 and IFN- genes than the
lung tissue of CD18 cattle. In the CD18
cattle, expression of the IFN- and TNF- genes was no greater in
P. haemolytica-inoculated lungs than in PFS-inoculated lungs at 4 h p.i. The main difference between the two groups of calves, CD18+ and CD18, was suspected to be the
ability to sustain gene expression. The molecular mechanism of the
signal transduction of 2-integrins is not fully
understood (37). It is clear, however, that these proteins
play an important role in immune responses by coordinating various
immunological and mechanical stimulations via cytoskeletal proteins,
resulting in a stronger immune response by the host (36,
37). Flaherty et al. observed that 2-integrin
mediates signal transduction in response to LPS in a
2-integrin gene-transfected Chinese hamster ovary
fibroblast cell line (18). These data suggest that
2-integrins contribute in vivo to induce PIC (especially IFN- and TNF-) gene expression, as a consequence of P. haemolytica infection. Therefore, CD18 cattle could
not respond properly to the P. haemolytica infection. Since
RTX toxins bind to 2-integrins and induce apoptosis of target cells, we considered leukotoxin of P. haemolytica a
potentially important mediator (26, 44). However, we could
not determine whether P. haemolytica leukotoxin had a
significant role in this experiment.
Ackermann et al. reported that the number of resident inflammatory
cells in the alveolar septum of CD18 animals is
substantially greater than the number in CD18+ animals
(2). They proposed three possible mechanisms for neutrophil infiltration into the lung alveoli of CD18 cattle:
migration through porelike fenestrae, CD18-independent adherence, and
septal degradative processes (2). At 2 h p.i., the
increase of neutrophils in the lung of P. haemolytica-inoculated CD18 cattle, but not
CD18+ cattle, was statistically significant (P < 0.05). At 4 h p.i., both CD18+ and
CD18 animals had significant neutrophil infiltration
(P < 0.05). Neutrophils have been shown to be the
primary inflammatory cells that migrate to the infection site
(17). The higher percentage and faster infiltration of
inflammatory cells seen in the CD18 animals at 2 h
after inoculation with P. haemolytica may be a mechanism to
compensate for the immune malfunction of the host. One of the
characteristics of CD18 animals is elevated leukocyte
counts in the blood due to a striking neutrophilia (19, 23,
25). The leukocytosis may contribute to the high number of
leukocytes in the lung tissues of CD18 animals after
P. haemolytica inoculation by simply increasing the chance
of random migration. In contrast to neutrophils, the percentages of
macrophages in the lungs after challenge with P. haemolytica
were not significantly different at the two time points. Doerschuk et
al. also observed CD18-independent migration of neutrophils into the
lungs of rabbits challenged with Streptococcus pneumoniae (14, 16). Recently, it was demonstrated that neutrophils may transmigrate the endothelium by activation of C5a and adhesion ligands
such as E-selectin, independent from CD18 (2, 21). Furthermore, neutrophils within the alveolar septum may release many
tissue-damaging materials such as proteases, fatty acid metabolites, and radical oxygen metabolites, thus facilitating leukocyte
infiltration into parenchymal tissue regardless of CD18 expression
(2).
This study suggests that even though leukocytes of infected
CD18 animals can transmigrate into the lungs, the cells
are unable to clear invading pathogens efficiently because of the
impairment of selective immune functions. Therefore, the
CD18 animals have more episodes of infections and more
persisting infections.
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ACKNOWLEDGMENTS |
This work was supported in part by USDA/NRI/CSREES grant 970-2653 and by the Immunology of Ruminant Perinatal Diseases (Mastitis) CRIS of
the USDA/ARS-National Animal Disease Center.
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FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Veterinary Pathology, 2738 Veterinary Medicine, Iowa State University, Ames, IA 50011-1250. Phone: (515) 294-3647. Fax: (515) 294-5423. E-mail: mackerma{at}iastate.edu.
Present address: Department of Cell and Molecular Biology, House
Ear Institute, Los Angeles, CA 90057.
Present address: Animal Health Research, Pfizer, Inc. Terre Haute,
IN 47808.
Editor:
E. I. Tuomanen
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Infection and Immunity, July 2000, p. 4274-4281, Vol. 68, No. 7
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
