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Journal of Virology, December 2000, p. 11966-11971, Vol. 74, No. 24
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Effects of Tumor Necrosis Factor Alpha on Sin
Nombre Virus Infection In Vitro
Svetlana F.
Khaiboullina,1
Dale M.
Netski,1
Peter
Krumpe,2 and
Stephen C.
St. Jeor1,*
Department of Microbiology and Cell and
Molecular Biology Program, School of Medicine, University of
Nevada
Reno,1 and Veterans Affairs
Sierra Nevada Health Care System,2 Reno, Nevada
Received 5 June 2000/Accepted 26 September 2000
 |
ABSTRACT |
Previous data indicate that immune mechanisms may be involved in
developing capillary leakage during Sin Nombre virus (SNV) infection.
Therefore, we investigated production of tumor necrosis factor alpha
(TNF-
) by human alveolar macrophages and human umbilical vein
endothelial cells (HUVEC) after infection with SNV. In addition, we
examined the effect of TNF- on HUVEC monolayer leakage. Our results
reveal that although TNF- decreases accumulation of
viral nucleoproteins, TNF- levels do not change in SNV-infected
cells. In addition, supernatants from SNV-infected human alveolar
macrophages did not cause a significant increase in endothelial
monolayer permeability.
| |
TEXT |
Hantaviruses are enveloped viruses
with a diameter of 120 nm and contain a trisegmented negative-strand
RNA genome (32). Hantaan virus and Sin Nombre virus (SNV)
are associated with the most severe forms of hantavirus infection in
humans, hemorrhagic fever with renal syndrome (HFRS) and hantavirus
pulmonary syndrome (HPS), respectively. Autopsy findings of HFRS and
HPS victims typically reveal the common feature of increased
permeability in microvascular beds, suggesting that the vascular
endothelium may be a prime target for virus infection. However,
investigations did not reveal endothelial cell necrosis attributable to
hantavirus replication (5, 41). These data represent a major
paradox of hantavirus infection: development of capillary leakage
without visible endothelial cell damage.
A number of observations have suggested that immune mechanisms play a
central role in development of HFRS (5, 43). Shortly after
onset of disease, activation of the humoral immune response results in
formation of specific immunoglobulin M (IgM) and IgG antibodies, which
leads to deposition of immune complexes in kidney glomerular capillary
basal membranes (41). During the febrile phase, T-cell
activation has been demonstrated by flow cytometry (5). This
activation is temporally associated with lymphocytosis and the
appearance of atypical lymphocytes in the peripheral blood (13). At the same time, a decrease in the CD4/CD8 lymphocyte ratio as a result of CD8 lymphocyte proliferation can be observed in
blood samples from HFRS patients (4). With the exception of
parameters reflecting renal failure, laboratory findings for HPS
patients are basically similar to those for HFRS patients (17).
Recently, an increase in the levels of tumor necrosis factor alpha
(TNF-) in plasma during the acute phase of hantavirus infection was
reported (19, 21). Immunohistochemical staining revealed
TNF--positive cells in lung tissue of patients with HPS who died and
in kidney biopsies of HFRS patients (27, 38). TNF- is a
macrophage-derived cytokine first described as a mediator of tumor
necrosis in mice (1). Pathological changes following TNF-
infusion include pulmonary inflammation, hemorrhage, microaggregation of leukocytes, and migration of polymorphonuclear leukocytes into the
pulmonary microcirculation system (27). Endothelial
cells exposed to TNF- increase procoagulant activity and
adhesiveness to lymphocytes and polymorphonuclear cells
(29). Also, TNF- treatment of endothelial cells in vitro
results in increased endothelial cell monolayer permeability without
visible cytopathic effect. It has been suggested that this effect of
TNF- could be a result of cytoskeleton changes in endothelial cells
(35). TNF- is also a strong activator of macrophages. It
stimulates migration, phagocytic activity, cytotoxic
activities, respiratory burst, and degranulation of phagocytes
(18, 22, 29). Increased levels in serum samples from HPS
patients and the presence of TNF- positive cells in lung biopsies
from patients with fatal HPS suggest that it may cause lung capillary
leakage. These experiments were initiated to determine if in vitro
infection with SNV induced changes in TNF- levels.
Effect of TNF- on the accumulation of SNV nucleocapsid protein
in Vero E6 cells.
Since Vero E6 cells are known to support the
replication of hantaviruses, we first examined the effect of TNF- on
nucleocapsid protein accumulation of SNV (SNV strain Convict Creek 107 [CC107], kindly provided by Connie Schmaljohn). Vero E6 cells were
grown in Iscove's medium with 2% fetal bovine serum. Recombinant
TNF- (50 ng/ml) (107 U/ml; Genzyme, Cambridge,
Mass.) was added to culture media after infection of Vero E6 cells with
SNV. Four days postinfection, fresh medium containing TNF- was added
to the culture medium. At various times postinfection, cells were
harvested and the accumulation of virus nucleocapsid protein was
examined by Western blotting. Equivalent loading of each lane of sodium
dodecyl sulfate-polyacrylamide gels was achieved by quantitation of
protein using a modified Lowry protein assay (Pierce, Rockford, Ill.)
and was verified by Coomassie blue staining of the gel. Nucleoprotein
monoclonal antibody GB04-BF07 (1:1,000; antibody from T. Ksiazek,
Centers for Disease Control and Prevention, Atlanta, Ga.) was incubated with membranes at room temperature overnight. Antigen-antibody complexes were identified with goat anti-human horseradish peroxidase (HRP)-conjugated antibodies (Vector Laboratories, Inc., Burlingame, Calif.) and developed under standard HRP substrate conditions (Vector
Laboratories, Inc.).
TNF- decreased accumulation of virus nucleocapsid protein in Vero E6
cells 1, 3, 4, 5, 6, and 7 days postinfection (Fig. 1) but did not affect the percentage of
infected cells or induce a visibly apparent cytopathic effect in
treated Vero E6 cells (data not shown). To study the effect of lower
concentrations of TNF-, 50, 10, and 1 ng/ml (5 × 104, 104, and 103 U/ml,
respectively) were utilized for treatment of infected Vero E6 cell
monolayers. In this experiment, fresh medium containing TNF- was not
added on day 4 of infection. All concentrations of TNF- had a
suppressive effect on virus nucleocapsid accumulation in Vero E6 cells
at 1, 3, 4, and 5 days postinfection. No differences in the levels of
virus nucleocapsid protein accumulated were detected 6 and 7 days after
infection (Fig. 2). This is likely caused
by the breakdown of TNF- after 5 days postinfection.
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FIG. 1.
Western blot analysis of the effect of TNF- on
accumulation of SNV nucleocapsid protein in Vero E6 cells. SNV
nucleocapsid protein was detected with sera from HPS convalescent
patients. Vero E6 cells were treated with 50 ng of TNF- per ml or
not treated with TNF- as a control. New culture medium was added to
the culture medium 4 days postinfection (P.I.), and a new aliquot of
cytokine was added.
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FIG. 2.
Western blot analysis of the effect of TNF- on
accumulation of SNV nucleocapsid protein in Vero E6 cells. Vero E6
cells were treated with 50, 10, and 1 ng of TNF- per ml or not
treated with TNF- as a control. There was no addition of new culture
medium to the culture medium 4 days postinfection.
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TNF-
increases nitric oxide synthase mRNA expression and nitric
oxide production in cells (
2,
34,
40). Since nitric
oxide is a nonspecific antiviral agent (
24), an increase in
its concentration in infected cells may explain the suppressive
effect of this cytokine on SNV nucleocapsid accumulation. To
investigate
this hypothesis, we utilized the nitric oxide synthase
inhibitor
N(G)-monomethyl-
L-arginine (a kind
gift from J. Maciejewski, National
Institutes of Health, Bethesda, Md.)
alone and in combination
with TNF-
. In addition, we used gamma
interferon (IFN-
) (1,000
U/ml; gift from J. Maciejewski), a
well-known antiviral cytokine
(
6), for comparative analysis
with TNF-
on suppression of
SNV nucleocapsid accumulation in Vero E6
cells (Fig.
3A). In this
experiment,
TNF-
was added immediately after infection and on
day 4 postinfection. TNF-
(1 ng/ml) had a suppressive effect
on the
accumulation of SNV nucleoprotein in Vero E6 cells at 3,
4, 5, 6, and 7 days postinfection. Nitric oxide synthase inhibitor
did not eliminate
the suppressive effect of TNF-
on SNV nucleocapsid
protein
accumulation. IFN-
(1,000 U/ml) decreased the accumulation
of SNV
nucleoprotein in infected cells at 3, 4, 5, 6, and 7 days
after
infection. The effect of IFN-
exceeded the activity of
TNF-
.
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FIG. 3.
Western blot analysis of the effects of TNF-,
N(G)-monomethyl-L-arginine (MMA), IFN-, and
pentoxyfilline on accumulation of SNV nucleocapsid protein in Vero E6
cells. (A) Vero E6 cells were treated with TNF- (1 ng/ml),
TNF- and MMA (5 µM), or IFN- (1,000 U/ml) or not treated as a
control. P.I., postinfection. (B) Vero E6 cells were treated with
TNF- (1 ng/ml) or pentoxyfilline (PTF) (5 mM) alone or combined;
some cells were not treated as a control. Four days postinfection, new
culture medium was added to the culture medium, and new aliquots of
cytokine and PTF were added.
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Investigations of the last decade revealed that pentoxifylline, a
potential antiinflammatory drug, abolished the effects of
TNF-
(
7,
28,
37). The accumulation of viral nucleoprotein
in the
presence of pentoxyfilline (5 mM; Sigma, St. Louis, Mo.)
alone or in
combination with TNF-
(10 ng/ml) was investigated
in SNV-infected
Vero E6 cells. TNF-
decreased accumulation of
viral nucleoprotein in
Vero E6 cells at 7 days post- infection.
Pentoxifylline alone did not
affect the accumulation of SNV nucleoprotein
7 days after infection.
The combination of cytokine and pentoxifylline
reversed the effect of
TNF-
and restored the level of viral nucleocapsid
protein to that of
the control (Fig.
3B). TNF-
-treated Vero E6
cells produced
slightly fewer plaques (data not shown) than the
control
(uninfected)
cells.
Treatment of human umbilical vein endothelial cells (HUVEC)
with TNF-
(10 ng/ml) decreased the accumulation of SN virus
nucleocapsid
protein in HUVEC 1, 3, 4, 5, 6, and 7 days postinfection,
and
no cytopathic effect was observed in infected-cell monolayers
(data
not
shown).
Effect of SNV infection and TNF- treatment on permeability of
HUVEC monolayer.
Modified Boyden chamber systems were used to
determine if SNV infection could alter endothelial cell monolayer
permeability. HUVEC were isolated from umbilical cords by the
method of Jaffe and colleagues (16) and used between
passages 2 and 4. Cells were plated on membrane inserts and placed in
24-well plates to comprise upper and lower compartments. Transmembrane
diffusion of HRP was used to detect changes in permeability of
endothelial monolayers, as described by Feldmann and colleagues
(9). When the HUVEC monolayers reached confluence (2 or 3 days), cells were infected with SNV at a multiplicity of infection of
0.01. Immunostaining of infected-cell monolayers revealed
that about 90% of HUVEC expressed SNV proteins 10 days
after infection (data not shown). SNV infection of HUVEC monolayer did
not cause statistically significant leakage (Fig.
4). However, during the observation
period, the concentration of HRP in the lower compartment of
infected-cell monolayers was always higher than in the uninfected
control. Although not statistically significant, this tendency may
reflect activation of endothelial cells after SNV infection. There was
no detectable cytopathic effect caused by SNV replication that could
explain this phenomenon.
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FIG. 4.
Effect of SNV infection on the leakage of endothelial
cell monolayer. Changes in optical density, using light with a
wavelength of 470 nm, over time are shown for SNV-infected (stippled
squares) and control (uninfected) (solid diamonds) HUVEC monolayers.
Each point is the mean of three separate experiments (two samples per
experiment). The means were compared by an unpaired t test,
and a P value of <0.05 was considered statistically
significant.
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To determine the effect of TNF-
on vascular endothelial cell
monolayer leakage, cytokine (50 ng/ml) was added to the upper
compartment and the permeability of HUVEC monolayers was examined.
The
choice of cytokine concentration was based on data from Feldmann
and
colleagues (
9) and Ishii and colleagues (
14), who
reported
that no increase of endothelial cell permeability occurred at
concentrations of TNF-
below 4 ng/ml. However, TNF-
(10 ng/ml)
caused a stable suppressive effect on the accumulation of SNV
nucleoprotein in previous experiments. In our experiments, TNF-
showed statistically significant (P < 0.05, P < 0.001)
increases
in HUVEC monolayer permeability 5 and 24 h after
initiation of
the experiment (Fig.
5).
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FIG. 5.
Effect of TNF- on endothelial cell monolayer leakage.
Changes in optical density, using light with a wavelength of 470 nm,
over time are shown for untreated endothelial cell monolayer (open
bars) and endothelial cell monolayer after treatment with TNF- (50 ng/ml) (solid bars). Values that are significantly different from the
control values are indicated by asterisks (*, P < 0.05; **, P < 0.001).
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Infection of human alveolar macrophages with SNV.
An earlier
study (43) reported alveolar macrophages expressing SNV
antigens in the lungs of patients with HPS. To determine whether
macrophages can be infected with SNV, the following experiment was
done. Human alveolar macrophages were isolated from bronchoalveolar lavage (BAL) following routine diagnostic procedures at the Veterans Affairs Sierra Nevada Health Care System, Reno, Nev. The University of
Nevada Biomedical Research Committee approved this project, and
patients gave informed consent. BAL was performed using an Olympus B4
bronchoscope wedged in distal airways and four 50-ml aliquots of normal
saline. Alveolar macrophages were separated from human BAL contents by
Ficoll density gradient centrifugation, and cells were plated into
six-well tissue culture plates. To avoid contamination, an
antibiotic-antimycotic mixture (Sigma) was used. On average, 2 to 5 million cells were recovered from each lavage sample. Cells were
divided equally to form two groups: control and SNV infected. After
1 h of adsorption, unattached virus was removed by extensive
washing and new medium was added. Supernatant (200-µl) aliquots were
collected at 4 and 7 days postinfection to determine the amount of
infectious virus present. At 7 days postinfection, cells were washed,
fixed, and stained with immune convalescent HPS sera to reveal
SNV-positive cells. Human alveolar macrophages are permissive to SNV
infection, as illustrated by the punctate staining pattern
(approximately 65% cells were positive) and localization of viral
antigens in the cytoplasm of infected cells (Fig. 6A and
B). No viral antigens were observed in
uninfected control cells (Fig. 6C). To detect virus production by human
alveolar macrophages, Vero E6 monolayers were incubated with macrophage culture supernatants for 1 h at 37°C. After infection, Vero E6 cells were washed, overlaid with 0.6% agarose, and incubated for 14 days. Agarose was removed, and cells were washed, fixed, and stained.
Human alveolar macrophages produced relatively low levels of SNV (<0.1
PFU/ml) (data not shown).
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FIG. 6.
SNV infection of human lung alveolar macrophages
isolated from BAL. Cells were infected with SNV stock (multiplicity of
infection of 0.01) and cultured for 7 days. SNV proteins were detected
by immunostaining with convalescent HPS serum. Immunostaining results
were visualized with a Nikon ES 800 microscope using differential
interference contrast microscopy. Images were captured with an
integrating charge-coupled device camera (Photonic Science, Millham,
England) and Image Pro Plus image analysis software (Media Cybernetics,
Silver Springs, Md.). Images were sharpened with Micro-tome version 4.0 (Vay-Tek, Inc., Fairfield, Iowa). (A) Human alveolar macrophages
infected with SNV. The presence of SNV antigens is revealed by red
alkaline phosphatase staining. (B) SNV-infected alveolar macrophages
illustrating the characteristic punctate staining pattern and
cytoplasmic localization of viral antigens. (C) Uninfected human lung
alveolar macrophages. Magnifications, ×200 (A and C) and ×400 (B).
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Detection of TNF- production by SNV-infected and LPS-treated
human alveolar macrophages.
Isolated human alveolar macrophages
were counted and added to six-well plates at a density of
106 cells/well. After 24 h of incubation, cells were
infected with SNV or treated with lipopolysaccharide (LPS) (1µg/ml;
Sigma). Four days after treatment, supernatants were collected for
quantitative enzyme-linked immunosorbent assay analysis using a
Quantikine ELISA Kit (R&D System, Minneapolis, Minn.).
SNV-infected human alveolar macrophages produced
significantly less TNF- than alveolar macrophages treated with
LPS (Fig. 7). Interestingly, alveolar macrophages from some donors did not produce any detectable TNF- in
response to virus infection, whereas the same cells developed a strong
cytokine response upon LPS treatment.
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FIG. 7.
Detection of TNF- in supernatant from SNV-infected
and LPS-treated human alveolar macrophages. Human alveolar macrophages
were not treated (bar 1), infected with SNV (bar 2), or treated with
LPS (bar 3). Values that are significantly different from the control
values are indicated by asterisks (**, P < 0.001).
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Effect of supernatant from SNV-infected and LPS-treated alveolar
macrophages on HUVEC monolayer leakage.
The supernatant culture
fluids from infected and LPS-treated human alveolar macrophages were
added to the upper compartment of 24-well plates of confluent HUVEC
monolayers. Supernatant from SNV-infected human alveolar macrophages
did not induce statistically significant changes in HUVEC monolayer
permeability. However, a statistically significant increase of HUVEC
monolayer leakage was observed 24 h after the addition of supernatant
from LPS-treated alveolar macrophages (Fig.
8). It is well-known that inflammatory cytokines may regulate virus gene expression and virus protein production. For example, TNF- inhibits hepatitis B virus gene expression in transgenic mice (11) and human
immunodeficiency virus type 1 replication in peripheral blood monocytes
and alveolar macrophages (20). TNF- and IFN- act
synergistically to inhibit murine cytomegalovirus and herpes simplex
virus replication (8, 23). TNF- markedly inhibits
respiratory syncytial virus replication in a dose and time-dependent
manner (26). Also, treating MDCK cells with TNF- inhibits
influenza virus replication and protein synthesis (39). Our
data revealed that TNF- inhibits SNV nucleoprotein accumulation in
infected Vero E6 cells. TNF- exhibits suppressive effects at
concentrations as low as 1 ng/ml which is close to that produced
by infected lung macrophages in our experiments. The effect of
TNF- was reversible, and periodic addition of fresh medium
containing TNF- was required to maintain the suppressive effect.
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FIG. 8.
Increased permeability of endothelial cell monolayer
after the addition of culture supernatants. The cultures were untreated
endothelial cells (open bars) and human alveolar macrophages that were
treated with LPS (shaded bars) or infected with SNV (solid bars).
Changes in optical density, using light with a wavelength of 470 nm,
over time are shown. Values that are significantly different from the
control values are indicated by asterisks (**, P < 0.001).
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The suppressive effect of TNF-
on the accumulation of SNV
nucleoprotein was not mediated by induction of endogenous production
of
nitric oxide by infected cells. This finding is supported by
Rosenkranz-Weiss and colleagues (
31), who showed that
neither
TNF-
, IFN-
, or IL-1 alone is able to activate nitric
oxide synthase
and increase production of nitric oxide in cells;
however, a combination
of cytokines was effective. The suppression of
SNV nucleocapsid
accumulation in Vero E6 cells after TNF-
treatment
was not due
to activation of the IFN-
antiviral pathway, because SNV
nucleocapsid
accumulation in Vero E6 cells was almost completely
suppressed
by IFN-
, whereas suppression induced by TNF-
was not
that
pronounced.
To further investigate the mechanism behind TNF-
-related suppression
of SNV nucleoprotein accumulation in infected cells,
we tested the
influence of pentoxifylline on the level of virus
nucleocapsid in
infected cells. Investigations over the last decade
revealed the
ability of this drug to abolish the effects of TNF-
.
Thus,
pentoxifylline protected the L929 cell line against
TNF-
-mediated
cytotoxicity and cytostasis (
37). Ohdama
and colleagues (
28)
reported prevention of TNF-
-induced
suppression of endothelial
cell surface thrombomodulin expression after
incubation of cells
with pentoxifylline. In our experiments,
pentoxifylline alone
did not change the level of SNV
nucleocapsid. However, in combination
with TNF-
, it
reversed the suppressive effect of the cytokine.
The mechanism of
anti-TNF-
activity of pentoxifylline is not
fully understood, but
investigators proposed that the effect might
be associated with its
selective inhibition of postreceptor signaling.
For example,
pentoxifylline abrogates TNF-
-induced actin filament
polymerization,
which has been reported to participate in receptor
cycling
(
7).
The lowest concentration of TNF-
used in our experiments was 1 ng/ml. Of concern was whether this concentration of cytokine
could be
produced by infected alveolar macrophages in humans infected
with SNV.
Experiments with infected human alveolar macrophages
revealed that
cells from at least 3 of 10 (33%) donors produced
approximately 1 ng
of TNF-
per ml after SNV infection. Surprisingly,
we were not able
to detect release of TNF-
by alveolar macrophages
from seven donors
following infection with SNV in vitro. In contrast,
LPS treatment of
alveolar macrophages collected from the same
donors resulted in
dramatic increases of TNF-
release in supernatants
of cells from all
donors. The macrophage cultures from some individuals
responded with up
to 8 ng of cytokine released per ml after activation
with LPS. These
data indicate that productive SNV infection of
human alveolar
macrophages is not always associated with an increase
in TNF-
release and that cytokine production appears to depend
on individual
patient
reactivity.
Histological observations of tissue samples from people with HPS who
died reveal that hantaviruses do not cause detectable
cytopathic
effects on blood vessel endothelial cells, despite
the presence
of hantavirus antigens in these cells (
17,
42,
43). However,
recent investigations (
10,
15) found that
vascular
leakage could occur without endothelial cell damage leading
to cell
death, through destruction of the adherens-type junctions
between
endothelial cells and degradation of the fibrin layer
underneath that
supports growth and viability of the endothelium.
Productive infection
of endothelial cells by SNV did not result
in a significant increase of
endothelium monolayer leakage. However,
our study with infected
HUVEC monolayer permeability shows an
increased tendency
of monolayers to leak after SNV infection.
We propose that this
statistically insignificant but stable increase
in permeability of
HUVEC is a sign of structural changes in interendothelial
junctions or
fibrin production in response to SN
infection.
Results of vitro experiments showed that TNF-
alone could cause
endothelial monolayer leakage (
3). However, the
concentrations
of cytokine used in those experiments were significantly
higher
than that (1.8 ng/ml) produced in vitro by SNV-infected cells
(our data). Our data are supported by work done by Ishii and colleagues
(
14), who found that endothelial monolayer permeability did
not increase in response to TNF-
concentrations below 4 ng/ml.
TNF-
concentrations in serum samples from patients with hemorragic
fever caused by different agents (Puumala virus, Hantaan virus,
Junin
virus, etc.) (
12,
19) never exceeded 100 pg/ml. We believe
that because of the low production of TNF-
by alveolar macrophages
after SNV infection, this cytokine alone could not be considered
the
sole causative agent of lung
edema.
In conclusion, in this study we demonstrated the following. (i) TNF-
has a suppressive effect on the accumulation of SNV
nuclecapsid protein
in infected cells. (ii) Human alveolar macrophages
are permissive for
SNV infection and react with low production
of TNF-
. (iii)
Supernatant from infected human alveolar macrophages
fails to induce
endothelial monolayer leakage. (iv) SNV infection
of endothelial cells
results in an insignificant increase of permeability,
which could be a
sign of structural changes in interendothelial
junctions.
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ACKNOWLEDGMENTS |
This study was supported in part by NIH grants AI36418, AI39808, and
AI45059 and by the Medical Service and Research Service of the Veteran
Affairs Sierra Nevada Health Care System.
We thank M. Hall for helpful discussions and critical reading of the manuscript.
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FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Microbiology, University of NevadaReno, Reno, NV 89557. Phone: (775) 784-4123. Fax: (775) 784-1620. E-mail: stjeor{at}med.unr.edu.
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Journal of Virology, December 2000, p. 11966-11971, Vol. 74, No. 24
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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