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Journal of Virology, April 2000, p. 3399-3403, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Virus Clearance through Apoptosis-Dependent
Phagocytosis of Influenza A Virus-Infected Cells by
Macrophages
Ippei
Fujimoto,1
Jiehong
Pan,2
Takenori
Takizawa,3 and
Yoshinobu
Nakanishi1,*
Graduate School of Natural Science and
Technology, Kanazawa University, Kanazawa, Ishikawa
920-0934,1 Department of Anatomy,
Kanazawa Medical University, Uchinada, Ishikawa
920-0265,2 and Institute for
Developmental Research, Aichi Human Service Center, Kasugai, Aichi
480-0392,3 Japan
Received 20 October 1999/Accepted 4 January 2000
 |
ABSTRACT |
Some cultured cell lines undergo typical apoptosis upon infection
with influenza virus. However, the release of replicated virus into the
culture medium does not change when apoptosis is inhibited. Since
apoptotic cells are heterophagically eliminated at early stages of the
apoptosis pathway, we anticipated that the coexistence of phagocytic
cells with virus-infected cells affects the extent of virus growth.
When influenza A virus-infected HeLa cells were mixed with activated
mouse peritoneal macrophages, efficient phagocytosis, which was
abrogated in the presence of a caspase inhibitor, occurred. At the same
time, the release of virus into the culture medium was completely
inhibited, and this required direct contact between virus-infected
cells and macrophages. Furthermore, an immunoelectron microscopic
analysis detected influenza virus particles associated with
phagosome-like structures within macrophages. These results indicate
that apoptosis-dependent phagocytosis of virus-infected cells may lead
to direct elimination of the pathogen.
| |
TEXT |
A variety of viruses induce
apoptosis in host cells upon infection, but the physiological role of
this phenomenon remains uncertain (9, 21). Influenza virus
causes apoptotic death of cultured cell lines (6, 11, 20) as
well as that of tissues in infected animals (12). Although
it has been postulated that the death of virus-infected cells should
lead to the spread of virus progeny to neighboring cells
(21), inhibition of apoptosis of influenza A virus-infected
cells by a caspase inhibitor does not affect the amount of replicated
virus released into the culture medium (19).
Since cells undergoing apoptosis are eventually engulfed and digested
by phagocytic cells (4, 22), elucidation of the mechanism
and consequences of phagocytosis of apoptotic virus-infected cells may
be required for understanding the physiological role of the induction
of apoptosis. Albert et al. recently reported that influenza
virus-infected monocytes are phagocytosed by dendritic cells in an
apoptosis-dependent manner and that this reaction leads to antigen
presentation resulting in stimulation of class I-restricted
CD8+ cytotoxic T lymphocytes (1). They further
showed that the same cells were phagocytosed by macrophages without
antigen presentation (2). The consequences of phagocytosis
of influenza virus-infected cells by macrophages have thus remained
uncertain. Here we examined the effect of macrophages on virus growth.
Infection and growth of influenza virus in HeLa cells.
HeLa S3
cells were maintained in Eagle's minimal essential medium-10% fetal
bovine serum at 37°C with 5% CO2 in air. The cells were
infected with a wild-type strain of influenza A/Udorn/72(H3N2) virus,
SP626, at a multiplicity of infection of 3 as described previously
(10). Influenza virus-infected HeLa cells were maintained in
poly-Lys-coated culture containers for 9 h, fixed with 2%
paraformaldehyde-0.1% glutaraldehyde-0.05% Triton X-100, rinsed in
methanol, washed with phosphate-buffered saline (PBS), and treated with
an anti-influenza A virus antiserum which was raised against purified
virions and recognizes nucleocapsid protein, M1, hemagglutinin, and
neuraminidase (16). The cells were then washed with 0.2%
Triton X-100-containing PBS, treated with a biotin-labeled anti-rabbit
immunoglobulin G (IgG) antibody (Vector), and washed as described
above. The samples were finally treated with fluorescein
isothiocyanate-conjugated avidin (Vector) and examined with a
fluorescence and phase-contrast microscope (BX50; Olympus). Nearly
100% of the cells showed positive signals (Fig.
1A) while the same antibody did not react
to mock-infected cells (data not shown). The virus titer, determined by
a plaque assay using MDCK cells and expressed as PFU as described
previously (20), in the culture medium increased, reaching a
maximum level at 24 h of infection (Fig. 1B). On the other hand,
completion of apoptosis as determined by various biochemical assays
required almost 48 h (data not shown), as reported previously
(7, 20). This suggests that viral replication proceeds
before host cell macromolecular synthesis becomes nonfunctional due to
apoptosis.
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FIG. 1.
Infection and growth of influenza virus in HeLa cells.
(A) Immunofluorescence analysis of virus-infected HeLa cells with an
anti-influenza virus antiserum. The cells at 9 h after infection
were stained with control rabbit IgG (left) or the anti-influenza virus
antibody (right) and examined by fluorescence microscopy. Scale
bar = 25 µm. (B) Time course of virus growth. The amount of
virus released into the culture medium was determined by a plaque
assay. The means and standard deviations of a typical example from
three independent experiments are presented.
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Phagocytosis of influenza virus-infected cells by macrophages.
Since cells treated with a variety of proapoptotic stimuli are engulfed
by phagocytic cells at early stages of the apoptotic pathway (4,
5, 13-15, 22), we anticipated that influenza virus-infected
cells might be susceptible to phagocytosis before production of
infectious virus begins. The phagocytosis assay with mouse peritoneal
macrophages was conducted as described previously (17, 18).
In brief, macrophages were isolated from peritoneal fluids of
thioglycollate-treated BDF1 mice and maintained in RPMI 1640-10% fetal bovine serum. HeLa cells were collected at 9 h after infection, a time at which the amount of virus released into the
culture medium is only 1/20 of the maximum level (see Fig. 1B), labeled
with biotin (NHS-LC-biotin; Pierce), and added to the macrophage
culture at a ratio of one HeLa cell to two macrophages. The mixed
culture was incubated for 30 min at 37°C, washed extensively, fixed
and permeabilized, supplemented with fluorescein isothiocyanate-labeled avidin, and examined with a fluorescence and phase-contrast microscope (Fig. 2A to D). The number of macrophages
that contained fluorescent signals was determined and expressed
relative to the total number of macrophages as the phagocytic index
(Fig. 2E). More than 30% of the macrophages appeared to incorporate
virus-infected cells, whereas they did not react with mock-infected
cells. These results suggested that macrophages selectively recognized
and phagocytosed influenza virus-infected cells. We next examined
whether this phagocytosis requires the occurrence of apoptosis in the
virus-infected cells. To test this, z-VAD-fmk, a caspase inhibitor, was
added to the culture from the beginning of infection. The drug reduced apoptosis, as determined by chromatin condensation, to 1/4 of the level
in the control (Fig. 3A) as described
previously (19), and at the same time, phagocytosis of the
z-VAD-fmk-treated cells decreased to a similar extent (Fig. 3B). This
indicated that macrophages phagocytosed virus-infected cells that were
undergoing apoptosis.
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FIG. 2.
Phagocytosis of influenza virus-infected cells by
macrophages. HeLa cells infected with influenza virus for 9 h (B
to D) or control mock-infected cells (A) were subjected to a
phagocytosis assay with mouse peritoneal macrophages. Fluorescence and
phase-contrast views (A, B, and D) and a phase-contrast view (C) are
shown. Scale bars: A and B, 25 µm; C and D, 10 µm. (E) The
phagocytic index means and standard deviations of a typical example
from three independent experiments are presented.
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FIG. 3.
Effect of a caspase inhibitor on apoptosis and
phagocytosis of influenza virus-infected cells. HeLa cells were
infected with influenza virus for 15 h in the presence of caspase
inhibitor z-VAD-fmk (Peptide Institute), and the extents of apoptosis
(A) and phagocytosis by macrophages (B) were determined. C, results
with mock-infected cells.
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|
Inhibition of virus growth in the presence of macrophages.
We
then examined whether virus growth is affected in the presence of
macrophages. HeLa cells were infected with influenza virus and added to
a macrophage culture after 9 h. The coculture was further
maintained, and the virus titer in the culture medium was determined at
24 and 48 h after infection. The virus titer in the medium of the
cocultures showed no increase and instead gradually decreased, while
that in a control culture without macrophages increased as the
culturing time increased (Fig. 4A). These
results indicated that release of influenza virus into the culture
medium was completely inhibited when virus-treated cells were cultured in the presence of macrophages and strongly suggested that this was due
to phagocytosis of infected cells by macrophages. However, the
possibility remained that soluble factors secreted from macrophages caused decreased replication and/or release of virus. Virus-treated HeLa cells and macrophages were therefore placed on opposite sides of a
permeable membrane, and virus growth was monitored. The results clearly
showed that direct association between virus-infected cells and
macrophages is required for inhibition of virus growth (Fig. 4B).
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FIG. 4.
Inhibition of influenza virus growth in the presence of
macrophages. (A) HeLa cells infected with influenza virus for 9 h
were further cultured in the absence (open circles) or presence (closed
circles) of macrophages, and the virus titer in the culture medium was
determined. The means and standard deviations of a typical example from
three independent experiments are presented. (B) HeLa cells infected
with virus for 9 h and macrophages were placed on opposite sides
of a permeable membrane (0.4-µm pores, Millicell-CM; Millipore), and
the virus titer in the culture medium was determined after 15 h.
The means and standard deviations of a typical example from three
independent experiments are presented.
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Association of influenza virus with phagosome-like structures in
macrophages.
We next used electron microscopy to directly detect
virus particles in macrophages that engulfed virus-infected cells (Fig. 5). A triple fixation method
(3) was adopted to detect influenza virus particles. HeLa
cells were fixed with 0.1 M phosphate buffer (pH 7.2) containing 2%
glutaraldehyde for 2 h at 4°C, washed, and treated with 1%
OsO4 for 1 h at 4°C. The cells were then washed with
0.1 M sodium acetate, further fixed with 0.5% uranyl acetate for 20 min at 4°C, and washed again with 0.1 M sodium acetate. The fixed
cells were scraped off culture containers, mixed with 2% agarose, and
pelleted by centrifugation. After the agarose solidified, a piece of it
was dehydrated with an ethanol series and embedded in Quetol 653, an
epon resin (Nisshin EM), and ultrathin sections were prepared with a
diamond knife. The sections were treated successively with 4% uranyl
acetate and lead citrate and examined with an electron microscope
(JEM-1200EXII; JEOL). When HeLa cells infected with virus for 9 h
were examined, electron-dense particles with a size and shape similar
to those of influenza virus were visible along the periphery (indicated
by arrows in Fig. 5A) while they were undetectable in mock-infected
cells (Fig. 5B). To examine if those particles were influenza virus,
immune electron microscopic analyses were conducted with the
anti-influenza virus antiserum. Ultrathin sections prepared as
described above were mounted on a nickel grid and treated with 1%
hydrogen peroxide and then with PBS containing 0.1% Tween 20-1%
bovine serum albumin-0.1% sodium azide. The samples were then treated
with the antiserum for 1 h at room temperature and washed. They
were supplemented with 10-nm gold particle-conjugated anti-rabbit IgG
(British Biocell), incubated for 1 h at room temperature, washed,
and examined by electron microscopy. Many particles were positive for
gold particles when treated with the anti-influenza virus antibody
(Fig. 5C) but not when treated with a control antibody (Fig. 5D).
Examination of the cells after the phagocytosis reaction revealed
macrophages that interact with apoptotic virus-infected cells using
pseudopodia (Fig. 5E and F). Some macrophages contained materials that
were high in electron density and surrounded by membranes (Fig. 5G and
H), suggesting that they were apoptotic cells within phagosomes. Moreover, the engulfed materials were associated with influenza virus
particles (indicated by arrows in Fig. 5G and H). These results
indicated that macrophages phagocytosed influenza virus together with
infected host cells.
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FIG. 5.
Presence of influenza virus within phagosome-like
structures in macrophages. Influenza virus-infected HeLa cells (at
9 h) and macrophages after phagocytosis reactions were examined by
electron microscopy. Shown are the periphery of a virus-infected (A) or
mock-infected (B) HeLa cell (particles detectable only with
virus-infected cells are indicated with arrows); an immunoelectron
microscopic analysis of virus-infected HeLa cells with anti-influenza
virus (C) or control (D) antibody; (E) a virus-infected HeLa cell
(left) and a macrophage (right); (F) a higher magnification view of
panel E (the arrows point to virus particles); and (G and H) a
phagosome-like structure within a macrophage (the arrows point to virus
particles). Scale bars: A and B, 0.5 µm; C and D, 0.1 µm; E, 2 µm; F and G, 0.5 µm; H, 0.1 µm.
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Taken together, the present findings showed that influenza
virus-infected HeLa cells are phagocytosed by macrophages and that the
phagocytosis depends on the occurrence of apoptosis. This resulted in
the inhibition of virus growth, suggesting that the virus, together
with its host cells, was digested in macrophages. These findings
suggest that apoptosis of influenza virus-infected cells induces
inhibition of virus growth and ultimately protects the organism from
viral diseases. Alveolar macrophages and polymorphonuclear leukocytes
were shown to be responsible for inhibition of influenza virus growth
in the lungs of virus-infected mice, although it is uncertain that
virus clearance was caused by phagocytosis of virus-infected cells
(8). It is important to expand this proposed system under
the in vivo situation. Since phagocytosis of influenza virus-infected
cells by dendritic cells leads to antigen presentation toward
lymphocytes (1, 2), induction of apoptosis upon virus infection would allow the organism to escape from the pathogen via two pathways.
| |
ACKNOWLEDGMENTS |
This study was supported by grants from the Organized Research
Combination System of the Science and Technology Agency of Japan and
from the Hokuriku Industrial Advancement Center.
We thank A. Shiratsuchi for advice about macrophage preparation and
phagocytosis assays; K. Hirai, S. Iseki, and Y. Hosaka for help and
comments about electron microscopy; and K. Shimizu for the
anti-influenza virus antiserum.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Graduate School
of Natural Science and Technology, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-0934, Japan. Phone: 81-76-234-4481. Fax: 81-76-234-4480. E-mail:
nakanaka{at}kenroku.kanazawa-u.ac.jp.
| |
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Journal of Virology, April 2000, p. 3399-3403, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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