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Journal of Virology, September 2000, p. 8135-8139, Vol. 74, No. 17
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Reovirus-Induced Apoptosis Is Mediated by
TRAIL
Penny
Clarke,1
Suzanne M.
Meintzer,1
Spencer
Gibson,2,3
Christian
Widmann,2,3
Timothy P.
Garrington,2,3
Gary L.
Johnson,2,3,4 and
Kenneth L.
Tyler1,5,6,*
Departments of
Neurology,1
Pharmacology,4 and Medicine,
Microbiology and Immunology,5 University of
Colorado Health Sciences Center, and Denver Veteran's Affairs
Medical Center,6 Denver, Colorado 80262, and
Program in Molecular Signal
Transduction2 and Division of Basic
Sciences,3 National Jewish Center for
Immunology and Respiratory Medicine, Denver, Colorado 80206
Received 13 April 2000/Accepted 9 June 2000
 |
ABSTRACT |
Members of the tumor necrosis factor (TNF) receptor superfamily and
their activating ligands transmit apoptotic signals in a variety of
systems. We now show that the binding of TNF-related, apoptosis-inducing ligand (TRAIL) to its cellular receptors DR5 (TRAILR2) and DR4 (TRAILR1) mediates reovirus-induced apoptosis. Anti-TRAIL antibody and soluble TRAIL receptors block reovirus-induced apoptosis by preventing TRAIL-receptor binding. In addition, reovirus induces both TRAIL release and an increase in the expression of DR5 and
DR4 in infected cells. Reovirus-induced apoptosis is also blocked
following inhibition of the death receptor-associated, apoptosis-inducing molecules FADD (for FAS-associated death domain) and
caspase 8. We propose that reovirus infection promotes apoptosis via
the expression of DR5 and the release of TRAIL from infected cells.
Virus-induced regulation of the TRAIL apoptotic pathway defines a novel
mechanism for virus-induced apoptosis.
| |
INTRODUCTION |
Studies using mammalian reoviruses
have provided fundamental insights into the molecular and genetic basis
of viral pathogenesis and virus-induced cell death. Reovirus infection
induces apoptosis in cultured cells in vitro (13, 15, 26)
and in target tissues in vivo, including the central nervous system,
heart, and liver (12, 13). Reovirus induces apoptosis by a
p53-independent mechanism that involves cellular proteases including
calpains (4), is dependent on reovirus-induced NF-
B
activation (3), and is inhibited by overexpression of Bcl-2
(15). Strain-specific differences in the capacity of
reoviruses to induce apoptosis are determined by the viral S1 gene
(26) and require viral binding to cell surface receptors but
not completion of the full viral replication cycle (15).
Reovirus-induced apoptosis correlates with pathology in vivo and is a
critical mechanism by which disease is triggered in the host
(12). Inhibition of apoptosis in vivo reduces the extent of
tissue injury (R. L. Debiasi et al., Am. Soc. Virol. Sci. Program
Abstr., abstr. W52-1, 1999), emphasizing the importance of
apoptosis in reovirus pathogenesis. We have thus used reovirus
infection to study mechanisms of virus-induced apoptosis.
Cellular death receptors (DRs) transmit apoptosis-inducing signals
initiated by specific death ligands, most of which are primarily
expressed as biologically active type II membrane proteins that are
cleaved into soluble forms. Fas ligand (FasL) activates Fas/CD95/Apo1,
tumor necrosis factor (TNF) activates TNFR1 (TNF receptor 1), Apo
3L/TWEAK activates DR3, and TRAIL (for TNF-related apoptosis-inducing
ligand; also called Apo2L) activates DR4 (TRAILR1) and DR5
(TRAILR2/TRICK2). Ligand-mediated activation triggers a cascade of
events that begins with DR oligomerization and the close association of
their cytoplasmic death domains (DDs). This is followed by
DD-associated interaction with adapter molecules and cellular proteases
critical to DR-induced apoptosis (reviewed in reference
1). In this paper we describe a novel mechanism for
virus-induced cell death involving the upregulation of DR5, the release
of TRAIL from infected cells, and subsequent TRAIL-mediated apoptosis.
| |
MATERIALS AND METHODS |
Cells, virus, and inhibitors.
HEK293 cells (ATCC CRL1573)
were grown in Dulbecco's modified Eagle's medium supplemented with
100 U each of penicillin and streptomycin per ml and containing 10%
fetal bovine serum. HeLa cells (ATCC CCL2) were grown in Eagle's
minimal essential medium supplemented with 2.4 mM
L-glutamine, nonessential amino acids, 60 U each of
penicillin and streptomycin per ml, and containing 10% fetal bovine
serum (Gibco BRL, Gaithersburg, Md.). FADD-DN cells express amino acids
80 to 208 of the Fas-associated DD (FADD) cDNA (with the addition of an
AU1 epitope tag at the N terminus), from the cytomegalovirus promoter
from pcDNA3 (Invitrogen, Carlsbad, Calif.). Reovirus (type 3 Abney
[T3A]) is a laboratory stock which has been plaque purified and
passaged (twice) in L929 (ATCC CCL1) cells to generate working stocks
(27). Virus growth was determined by plaque assay as
previously described (25).
Western blot analysis and antibodies.
Twenty-four hours
following infection with reovirus, cells were pelleted by
centrifugation, washed twice with ice-cold phosphate-buffered saline,
and lysed by sonication in 200 µl of a buffer containing 15 mM Tris
(pH 7.5), 2 mM EDTA, 10 mM EGTA, 20% glycerol, 0.1% NP-40, 50 mM
-mercaptoethanol, 100 µg of leupeptin and 2 µg of aprotinin per
ml, 40 µM Z-D-DCB, and 1 mM phenylmethylsulfonyl fluoride. The
lysates were then cleared by centrifugation at 16,000 × g for 5 min, normalized for protein amount, mixed 1:1 with sodium dodecyl sulfate (SDS) sample buffer (100 mM Tris [pH 6.8], 2% SDS,
300 mM -mercaptoethanol, 30% glycerol, 5% pyronine Y), boiled for
5 min, and stored at 
70°C. Proteins were electrophoresed by
SDS-10% polyacrylamide gels and probed with polyclonal antibodies directed against DR4 (366891N [PharMingen, San Diego, Calif.] and
sc-6823 [Santa Cruz Biotechnology, Santa Cruz, Calif.]), DR5 (210-730-C100 [Alexis Corporation, Pittsburgh, Pa.] and sc-7191 [Santa Cruz Biotechnology]), DCR-2 (33060-100; Biovision, Palo Alto,
Calif.), Fas (sc-714-G; Santa Cruz Biotechnology), and actin (CP01;
Oncogene, Cambridge, Mass.). Additional antibodies directed against
FasL (sc-834-G; Santa Cruz Biotechnology) and TRAIL (3210-732-R100 [Alexis Corporation] and antibody from Affinity Bioreagents, Golden, Color.) were used for antibody blocking experiments. Autoradiographs were quantitated by densitometric analysis using ImageQuant (Amersham Pharmacia Biotech, Inc., Piscataway, N.J.).
Apoptosis assays and reagents.
Forty-eight hours after
infection with reovirus, cells were harvested and stained with acridine
orange, for determination of nuclear morphology, and ethidium bromide,
to distinguish cell viability, at a final concentration of 1 µg/ml
each (5). Following staining, cells were examined by
epifluorescence microscopy (Nikon Labophot-2; B-2A filter; excitation,
450 to 490 nm; barrier, 520 nm; dichroic mirror, 505 nm). The
percentage of cells containing condensed nuclei and/or marginated
chromatin in a population of 100 cells was recorded. The specificity of
this assay has been previously established in reovirus-infected cells
using DNA laddering techniques and electron microscopy (26).
Soluble TRAIL was obtained from Upstate Biotechnology, Lake Placid,
N.Y. Soluble DRs Fc:DR4, Fc:DR5, and Fc:TNFR were obtained from Alexis
Corporation. Z-IETD-FMK (granzyme B inhibitor III), a specific
inhibitor of caspase 8 activity, was obtained from Clontech, Palo Alto, Calif.
| |
RESULTS |
Reovirus-induced apoptosis is mediated by TRAIL.
We
investigated the role of ligand-mediated apoptosis in reovirus-induced
cell death using two separate polyclonal antibodies directed against
TRAIL and antibodies directed against FasL and TNF to block ligand
binding during reovirus infection. HEK293 cells were pretreated with
antiligand antibodies (30 µg/ml) for 1 h before viral infection
(multiplicity of infection [MOI] of 10) and were maintained in
antibody-containing media following infection with reovirus. Antibody
was not present during viral infection. The percentage of apoptotic
cells was determined at 48 h postinfection. Anti-TRAIL antibodies,
but not antibodies directed against FasL (TRAIL versus FasL,
P = 0.008) or TNF (TRAIL versus TNF, P = 0.003) significantly inhibit reovirus-induced apoptosis
(Fig. 1A). Thus, anti-TRAIL
antibodies specifically inhibit reovirus-induced apoptosis.
Anti-TRAIL antibody also inhibits reovirus-induced apoptosis in L929
cells (Fig. 1A), indicating that TRAIL-mediated apoptosis is likely to
be a general feature of reovirus-induced apoptosis. Both anti-TRAIL
antibodies bound soluble ligand in Western blot analysis (results not
shown).
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FIG. 1.
TRAIL mediates reovirus-induced apoptosis. Anti-TRAIL
antibodies and soluble TRAIL receptors (Fc:DR4 and Fc:DR5) specifically
inhibit reovirus-induced apoptosis. HEK293 and L929 cells were
pretreated for 1 h with two different anti-TRAIL (TRAILa and
TRAILb) antibodies (A) or increasing concentrations of soluble TRAIL
receptors (B) before being infected with reovirus (MOIs of 10 and 50, respectively, for antibody and receptor experiments). After infection
cells were incubated in media containing antibody or receptor for
48 h before cells were harvested and the percentage of apoptotic
cells was determined. The graphs show percent apoptosis compared to
untreated cells in reovirus-infected minus mock-infected cells (A) and
the actual percent apoptosis in reovirus-infected minus mock-infected
cells (B). Error bars represent standard error of the mean. Antibodies
directed against TNF and FasL were used as controls in the antibody
blocking experiments. Soluble TNFR (Fc:TNFR) was used as a control in
the receptor experiments.
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|
TRAIL binding was further shown to be essential for reovirus-induced
apoptosis using the soluble TRAIL receptors Fc:DR4 and
Fc:DR5 (Fig.
1B). These molecules contain the extracellular domain
of DR4 or DR5
fused to the Fc portion of human immunoglobulin
G and inhibit
TRAIL-induced apoptosis by preventing TRAIL binding
to DR4 and DR5
present on the cell surface (
7). Cells were
pretreated with
soluble receptor for 1 h before virus infection
(MOI of 50) and
were maintained in receptor-containing media following
infection.
Soluble receptor was not present during viral infection.
Treatment of
cells with Fc:DR4 or Fc:DR5 (not shown) produces
a dose-dependent
inhibitory effect on reovirus-induced apoptosis
(Fig.
1B). Thus, Fc:DR4
and Fc:DR5 appear to be similar in potency
for TRAIL binding. Fc:DR4
(100 ng/ml) and Fc:DR5 (100 ng/ml) reduced
reovirus-induced apoptosis
by 65% (from 54% to 19%,
P = 0.048)
and by 70%
(from 54% to 16%), respectively. Soluble TNFR (Fc:TNFR;
100 ng/ml)
does not significantly inhibit reovirus-induced apoptosis,
indicating
that the inhibition is specific for the TRAIL-associated
receptors DR4
and DR5. In L929 cells, Fc:DR4, but not Fc:TNFR,
also significantly
inhibited reovirus-induced apoptosis by 57%
(from 81% to 35% [Fig.
1B]), again indicating that TRAIL-mediated
apoptosis is likely to be a
general feature of reovirus-induced
apoptosis. To confirm that antibody
or soluble receptor-mediated
inhibition of apoptosis was not due to any
effect of these reagents
on viral replication, we measured viral yield
in anti-TRAIL and
soluble receptor-treated cells and found no
significant difference
compared with untreated cells (results not
shown).
TRAIL is released from cells following infection with
reovirus.
Having shown that TRAIL is required for
reovirus-induced apoptosis, we next wanted to determine whether
cleaved, soluble TRAIL is released from in reovirus-infected cells.
Following infection of HEK293 cells with reovirus (MOI of 100), the
supernatant was collected and transferred onto HeLa cells,
which are
sensitive to TRAIL-induced apoptosis (Fig.
2). Supernatants
collected from
virus-infected HEK293 cells 24, 36, and 48 h postinfection
induce
apoptosis (18, 30, and 68%, respectively) when transferred
onto HeLa
cells. Apoptotic HeLa nuclei were assayed 24 h following
treatment
with supernatant from reovirus-infected HEK293 cells.
Supernatant-induced apoptosis of HeLa cells is inhibited 64% (from
68% to 31%,
P = 0.001) by soluble DR5 (Fc:DR5; 100 ng/ml [Fig.
2]) and by soluble DR4 (Fc:DR4; 100 ng/ml [results not
shown]),
indicating that the apoptosis seen in the HeLa cells
following
supernatant transfer is TRAIL specific. TRAIL is thus
released
from reovirus-infected cells and induces apoptosis in HeLa
cells.
The apoptotic effects of infected cell supernatants are not due
to the presence of infectious virus in the transferred supernatant
since addition of a neutralizing polyclonal antireovirus antiserum
that
blocks apoptosis induced by infectious virus (
26) does
not
block apoptosis induced in HeLa cells by supernatant transfer
(Fig.
2).
This antibody inhibits reovirus (MOI of 100)-induced
apoptosis in
HEK293 cells (Fig.
2).
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FIG. 2.
TRAIL is released from reovirus-infected cells. HEK293
cells were either mock infected or infected with reovirus (MOI of 100).
At various times postinfection (PI), supernatant from infected HEK293
cells was transferred onto TRAIL-sensitive HeLa cells. Apoptosis was
assayed in HeLa cells 24 h following supernatant transfer. The
graph shows the percent increase of apoptotic nuclei in HeLa cells
following treatment with supernatants taken from reovirus-infected,
compared to mock-infected, HEK293 cells. Error bars represent standard
errors of the mean. Soluble DR5 (Fc:DR5) and an antireovirus (anti-reo)
antibody were used as TRAIL specificity controls. The shaded bars
demonstrate that reovirus-induced (MOI of 100) apoptosis is blocked by
the antireovirus antibody in HEK293 cells.
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|
Expression of DR5 is up-regulated following infection with
reovirus.
Reovirus-induced apoptosis thus requires TRAIL binding,
and TRAIL is released from reovirus-infected cells. We next
investigated the expression of TRAIL receptors in reovirus-infected
cells. HEK293 cells were infected with reovirus (MOI of 100), harvested at various times postinfection, and examined by Western blot analysis. DR5 is detected in lysates extracted from reovirus-infected but not
mock-infected HEK293 cells. DR5 expression is first detected at 4 h postinfection. Expression peaks at 24 h postinfection and then
declines (Fig. 3). The expression of DR4
also increases in reovirus-infected cells, but with much less magnitude
and only at late times after infection (Fig. 3B). DR5 thus appears to
be the TRAIL receptor that is predominantly up-regulated following reovirus infection.
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FIG. 3.
DR5 is up-regulated during reovirus-induced apoptosis.
Cell lysates were prepared and examined by Western blotting using
antibodies directed against DR5 and actin (A). Following
autoradiography, densitometric analysis was performed (B). The graph
shows the increase in signal observed in reovirus-infected compared to
mock-infected cells for DR5 (black columns) and DR4 (shaded columns).
M, mock infection; PI, postinfection.
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|
Decoy receptor 1 (DcR-1; also called TRAILR3/TRID/LIT) and DcR-2
(TRAILR4) compete with DR4 and DR5 for TRAIL binding. These
decoy
receptors do not contain active intracellular DDs do not
transduse
apoptotic signals, and have antiapoptotic effects (
6,
17).
Neither DcR-1 nor DcR-2 expression is significantly altered
in
reovirus-infected cells (results not
shown).
Reovirus infection sensitizes cells to TRAIL-induced
apoptosis.
TRAIL-induced apoptosis is enhanced in cells
demonstrating an increase in the surface expression of DR4 and DR5
(7). Having shown that reovirus infection results in
increased expression of DR5 and to a lesser extent DR4, we next wished
to determine whether these increases occur at the cell surface by
demonstrating that reovirus sensitizes cells to TRAIL-induced
apoptosis. Cells were infected with reovirus (MOI of 10), treated with
TRAIL (200 ng/ml) at various times postinfection and assayed for
apoptosis 24 h later. Mock-infected HEK293 cells do not undergo
apoptosis when treated with TRAIL. However, following infection with
reovirus, HEK293 cells become sensitive to TRAIL-induced apoptosis
(Fig. 4), and the percentage of apoptotic
nuclei in TRAIL-treated, reovirus-infected cells is greater than that
in cells treated with reovirus alone (Fig. 4). At 12, 24, 30, and
48 h after infection with reovirus, TRAIL-treated cells
demonstrated 2.4-, 3.7-, 3.3-, and 1.8-fold increases in apoptosis,
respectively, compared to TRAIL-treated mock-infected cells. Since
TRAIL-induced apoptosis is apparent 12 h following infection with
reovirus and since the up-regulation of DR4 is not seen until 24 h
postinfection, this again suggests that it is the increased expression
of DR5 rather than DR4 that is the primary TRAIL receptor involved in
reovirus-induced apoptosis.
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FIG. 4.
Reovirus infection sensitizes cells to TRAIL-induced
apoptosis. The effectiveness of TRAIL (200 ng/ml)-induced apoptosis was
assayed in mock ()- or reovirus (+; MOI of 10)-infected cells. Cells
were treated with TRAIL (black bars) or left untreated (shaded bars).
At various times postinfection (P.I.), cells were assayed for the
presence of apoptotic nuclei. The graph shows the mean percentage of
apoptotic nuclei. Error bars represent standard errors of the mean.
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FADD and caspase 8 are involved in reovirus-induced apoptosis.
DRs mediate apoptosis through receptor-associated DD containing adapter
proteins, exemplified by FADD (also called Mort 1). These adapter
molecules contain their own DDs that bind to the clustered receptor
DDs, resulting from receptor-ligand binding (reviewed in reference
1). Studies with dominant negative (DN) mutants of
FADD (28) and cells derived from FADD gene knockout mice
(31) indicate that FADD is necessary for apoptosis mediated by Fas, TNFR1, and DR3 (1, 9, 28). Apoptotic signals induced by DR4 and DR5 also appear to be mediated either by FADD or a FADD-like
adapter molecule (1, 29). We constructed a HEK293 cell line
expressing DN FADD (FADD-DN) in order to inhibit FADD and therefore
DR-mediated apoptosis. Reovirus-induced apoptosis in HEK293 cells (and
in HEK293 cells expressing vector alone [not shown]) is reduced by
85% (from 80.3% to 12%, P = 0.0012) in
reovirus-infected HEK293 cells expressing FADD-DN (Fig.
5). These results confirm our findings
that reovirus-induced apoptosis involves cellular DRs.
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FIG. 5.
Reovirus-induced apoptosis involves FADD and caspase 8 activity. HEK293 cells expressing FADD-DN or HEK293 cells treated with
a specific inhibitor of caspase 8 (IETD) were infected with reovirus
(MOI of 50). Apoptosis was assayed 48 h postinfection. The graph
shows the mean percentage of apoptotic nuclei. Error bars represent
standard errors of the mean.
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|
DR-induced, FADD-mediated apoptosis requires the activity of caspase 8. Activation of caspase 8 requires association of its
death effector
domains with those of FADD. Activated caspase 8
then activates the
downstream effector caspases, including caspase
3 (reviewed in
references
16 and
23). To further
support the
role of the TRAIL/DR pathway in reovirus-induced apoptosis,
we
demonstrate that IETD-fmk (50 µM), a specific inhibitor of caspase
8, reduces reovirus-induced apoptosis by 48% (from 80.3% to 42%,
P = 0.372), indicating that caspase 8 is involved
in reovirus-induced
apoptosis (Fig.
5).
| |
DISCUSSION |
We have shown that reovirus-induced apoptosis requires TRAIL
binding to its apoptosis-inducing receptors DR5 and/or DR4. However, exogenous TRAIL (200 ng/ml) does not induce apoptosis in uninfected HEK293 cells since these cells do not express sufficient cell surface
DR4 or DR5. To induce apoptosis, reovirus must therefore up-regulate
both TRAIL and a death-associated TRAIL receptor. We therefore
determined that there is both an increase in the release of TRAIL and
an increase in the expression of DR5, and to a lesser extent DR4, in
reovirus-infected cells. It seems unlikely that the up-regulation of
both DR4 and DR5 is required for TRAIL-mediated expression in
reovirus-infected cells. The quicker and more dramatic increase in DR5
expression compared to DR4 expression suggests that DR5 is the major
receptor involved in triggering apoptosis. Furthermore, the increased
sensitivity of reovirus-infected HEK293 cells to TRAIL-induced
apoptosis is detectable 12 h following infection, whereas the
alteration in expression of DR4 does not occur until 24 h
postinfection. These results suggest that the contribution of DR4 to
reovirus-induced apoptosis may be a secondary event and that its
up-regulation in reovirus-infected cells may function to amplify the
effects of TRAIL/DR5 regulation.
We propose a model in which reovirus infection results in the
up-regulation of DR5 and the release of TRAIL, thereby activating the
TRAIL pathway of cell death (Fig. 6).
Similar to other DR-mediated apoptotic pathways, reovirus-induced
apoptosis requires the participation of an adapter molecule (FADD) and
the activation of the caspase cascade since it is reduced in the
presence of inhibitors of FADD or caspase 8 activity. We have recently
shown that reovirus-induced apoptosis requires the transcription factor
NF-B (3). Future studies will be directed at examining
the role of NF-B in the up-regulation of TRAIL and DR5 in
reovirus-infected cells.
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FIG. 6.
Reovirus induces the TRAIL apoptotic pathway in infected
cells by inducing the release of TRAIL and the up-regulation of DR5.
The consequent binding of TRAIL to DR5 then promotes FADD association
and the activation of caspase 8.
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|
Our results demonstrate the involvement of the TRAIL
apoptotic pathway in reovirus-induced cell death and provide
the first direct evidence for the involvement of this pathway in
virus-induced apoptosis. Additional support for the potential role of
DR4 and DR5 in virus-induced apoptosis comes from studies suggesting
that human immunodeficiency virus (HIV) infection increases the
expression of TRAIL and sensitizes T cells to TRAIL-mediated apoptosis
(10). Previous studies have suggested that other members of
the TNFR DR superfamily may also be involved in apoptosis induced in
cells infected with a variety of viruses. Alteration of the cell
surface expression of Fas may be involved in virus-induced, or viral
regulation of, apoptosis in cells infected with influenza virus
(21, 22), herpes simplex virus type 2 (19),
bovine herpesvirus 4 (30), adenovirus (24), and
HIV type 1 (2, 11). Similarly, apoptosis induced by
hepatitis B virus (20), HIV type 1 (8), bovine herpesvirus 4 (30), and parvovirus H-1 (14) may
involve the TNFR signaling pathway. TRAIL and TRAIL receptor expression
have been shown to mediate gamma interferon-induced antiviral activity (18), although the mechanism by which this occurs is unknown.
We propose that the regulation of TRAIL and its death-promoting
receptors is a primary mediator of apoptosis that is induced not only
following viral infection but also as a component of apoptosis-inducing
stress responses, including chemotherapy (7).
| |
ACKNOWLEDGMENTS |
This work was supported by Public Health Service grants
1RO1AG14071 and GM30324 from the National Institutes of Health, Merit and REAP grants from the Department of Veterans Affairs, and U.S. Army
Medical Research and Material Command grant USAMRMC98293015 (K.L.T.)
S.G. is a Leukemia Society fellow. The University of Colorado Cancer
Center provided core tissue culture and media facilities.
We thank Terrence S. Dermody and Jodi L. Connelly for helpful advice
during the development of this project.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Neurology (127), Denver VA Medical Center, 1066 Clermont St., Denver, CO 80220. Phone: (303) 393-2874. Fax: (303) 393-4686. E-mail: Ken.Tyler{at}uchsc.edu.
Present address: Institute de Biologie Cellulaire et de
Morphologie, Lausanne, Switzerland.
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Journal of Virology, September 2000, p. 8135-8139, Vol. 74, No. 17
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
