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Journal of Virology, August 2000, p. 7628-7635, Vol. 74, No. 16
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Efficient Lytic Infection of Human Arterial
Endothelial Cells by Human Cytomegalovirus Strains
M.
Kahl,1
D.
Siegel-Axel,2
S.
Stenglein,1
G.
,
Jahn,1 and
C.
Sinzger1,*
Department of Medical
Virology1 and Department of Internal
Medicine III,2 University of Tübingen,
D-72076 Tübingen, Germany
Received 23 March 2000/Accepted 11 May 2000
 |
ABSTRACT |
Endothelial cells (EC) are common targets of permissive infection
by human cytomegalovirus (HCMV) in vivo during acute disease. However,
studies of HCMV-EC interactions in vitro have generated discordant
results. While lytic infection of cultured venous EC has been well
established, Fish et al. (K. N. Fish, C. Soderberg Naucler,
L. K. Mills, S. Stenglein, and J. A. Nelson, J. Virol. 72:5661-5668) have reported noncytopathic persistence of the virus in
cultured aortic EC. We propose that interstrain differences in viral
host cell tropism rather than the vascular bed of origin of infected EC
might account for these discrepancies. In the present investigation we
compared the responses of EC derived from human adult iliac artery,
placental microvasculature, and umbilical vein to infection with
various HCMV strains. Regardless of the vascular bed of origin,
infection with EC-propagated HCMV strains induced 100% efficient
cytopathic change progressing to complete lysis of inoculated
monolayers. While fibroblast-propagated strains persisted at low titer
in infected arterial EC cultures, they were also cytolytic for
individual infected cells. The finding of cytopathic lytic infection of
arterial EC by HCMV implicates a mechanism of vascular injury in the
pathogenesis of HCMV infection.
| |
TEXT |
Endothelial cells (EC) are major
targets of human cytomegalovirus (HCMV) during acute infection of an
immunocompromised host (18). In addition to contributing to
hematogenous viral dissemination (7, 8, 13, 19, 23),
infected EC may trigger direct vascular injury if viral induced
cytopathogenicity occurs. In support of these in vivo data,
susceptibility of cultured human venous EC (HUVEC) to productive lytic
HCMV infection has been demonstrated (25). However, studies
of interactions of HCMV with human arterial EC (HAEC) have generated
conflicting results. Whereas reports about noncytopathic persistence of
HCMV in cultured aortic EC (6) raised the possibility of
different susceptibilities of EC depending on their vascular origin,
Knight et al. (9) have described similar
cytopathologies of HCMV in HUVEC, HAEC, and
microvascular EC with regard to adhesion molecule induction. The respective usage of fibroblast-propagated and EC-propagated HCMV
strains might provide an explanation for the discrepancies. While such
interstrain differences in the cytopathic potential of HCMV in HUVEC
are well established (11, 20, 22, 24), the lytic potentials
of various HCMV strains in HAEC have not yet been determined.
In the present investigation we have tested the hypothesis that
interstrain differences in viral host cell tropism, rather than
properties inherent to EC of different vascular origins, determine the
outcome of HCMV infection. To this end we have performed a detailed
analysis of viral replication kinetics, long-term evolution of
cytopathology, and lytic end points, comparing EC derived from human
adult iliac artery, placental microvasculature, and umbilical vein
following inoculation with various HCMV strains.
Efficient lytic infection of HAEC by EC-propagated HCMV
strains.
In a first set of experiments, HCMV strains VHL/E
(kindly provided by W. J. Waldman) (24) and
TB40/E (22) were tested for cytopathic potential in HAEC.
Both strains were propagated in HUVEC to preserve the natural
endothelial cytopathogenicity of the original isolates. To obtain
high-titer virus preparations, EC-propagated virus stocks were
inoculated with fibroblasts for a single round of infection,
harvested at 100% cytopathic effect (CPE), and made cell free by
centrifugation. HAEC were isolated from adult human iliac arteries of
bypass recipients by mechanically removing the endothelial layer as
previously described (1, 2) and were cultured in EGM-2
medium (Clonetics, Walkersville, Md.) containing 2% fetal calf serum
on culture flasks (Greiner, Frickenhausen, Germany) coated with 2%
gelatin. For infection, cells were preincubated for 2 h in
heparin-free medium, inoculated with cell-free virus at multiplicities
of infection (MOI) of 0.1, 1, and 10, and incubated for 90 min before
removal of the inoculum. The medium was replaced at 48-h intervals. The
kinetics of viral antigen expression in HAEC cultures was analyzed
by indirect immunoperoxidase detection of immediate-early antigen
(UL122/123; monoclonal antibody [MAb] E13; Biosoft, Paris, France),
early protein p52 (UL44; MAb BS510; Biotest, Dreieich, Germany),
and late viral major capsid protein (UL86; MAb 28-4; kindly
provided by W. Britt) in acetone-fixed cultures at various intervals
postinoculation (p.i.), using diaminobenzidine as the chromogen. CPEs
and lysis of infected cells were documented by sequential
phase-contrast micrographs up to day 32 p.i.; i.e., identical
frames of infected cultures were photographed daily with a Zeiss
Axiovert 135 microscope. The accuracy of the method can be judged from
Fig. 2D, where characteristic scratch structures were present on the
surface of the culture plate, and from Fig. 4, where characteristic
cell culture structures are indicated. All experiments described in
this paper were repeated at least three times with identical results.
Both strain TB40/E (Fig. 1 and
2B and D) and strain
VHL/E (data not shown) established a fully permissive infection in HAEC in vitro. At a high MOI (MOI of 10), the majority of cells were infected by the initial inoculum, and within 48 h the late stage of viral replication was observed (Fig. 1). By day 12 p.i., lysis of infected cells occurred, and lysis was completed by day 17 p.i.
(Fig. 2B). At a low MOI (0.1), only a minor fraction of cells were
infected. However, both strains TB40/E (Fig. 2D) and VHL/E (data not
shown) disseminated throughout HAEC monolayers, ultimately resulting in
100% CPE (by day 27 p.i.) as indicated by the appearance of
characteristic nuclear inclusions in 100% of the cells. Subsequently, lysis of the infected cultures occurred (by day 32 p.i.) (Fig. 2D), while mock-infected cultures remained intact (Fig. 2A and C).
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FIG. 1.
HCMV antigen expression in HAEC cells infected with HCMV
strain TB40/E at an MOI of 10. (A to D) Detection of immediate-early
antigen (MAb E13, UL122/123) 1 day after infection (A), of early
antigen p52 (MAb BS510, UL44) 4 days after infection (B), of late
antigen major capsid protein (MAb 28-4, UL86) 4 days after infection
(C), and of the irrelevant antibody anticytokeratin (control for
specificity of staining) 4 days after infection (D) in HAEC by the
indirect immunoperoxidase technique. (E) Time course of appearance of
viral antigens in infected HAEC.
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FIG. 2.
CPEs of HCMV strains TB40/E and TB40/F in HAEC cultures.
CPEs were documented by sequential phase-contrast micrographs of HAEC
cultures either mock infected (A and C), infected with HCMV strain
TB40/E at an MOI of 10 (B), infected with HCMV strain TB40/E at an MOI
of 0.1 (D), or infected with HCMV strain TB40/F at an MOI of 10 (E) at
the indicated days p.i. (dpi).
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Interstrain differences in HCMV infection of HAEC.
To test
whether the efficiency of infection in HAEC distinguishes
EC-propagated strains from fibroblast-propagated strains, quantitative analysis of cell-free infection and cell-associated infection of HAEC was performed, comparing fibroblast-propagated strains AD169, TB40/F (22), and VHL/F (kindly provided by
W. J. Waldman) (24) with HUVEC-propagated strains
TB40/E (22) and VHL/E (24). The efficiency
of cell-free HCMV infection was determined by limiting-dilution
analyses in human foreskin fibroblast (HFF) and HAEC cultures (Table
1). Cell-free supernatants of the various
virus strains were harvested from HFF cultures displaying 100%
late-stage CPE. Identical log step dilutions were incubated with HFFs
and HAEC in 96-well plates for 24 h. Cultures were then fixed, and
infected cells were detected by indirect immunoperoxidase staining of
viral immediate-early antigen. The infectivity of a given virus
preparation in HFFs or HAEC was calculated as the 50% tissue culture
infective dose (TCID50) per milliliter by the method of
Spearman and Kärber (described in reference
12). Cell-associated infectivity was determined by
focus expansion (FE) assays (Table 2) as
described previously (20). In FE assays, the potential of
HCMV to spread from late-stage infected cells to adjacent uninfected
HAEC or HFFs was quantified in cocultures. The number of infected cells
per focus (FEHAEC or FEHFF) at day 5 after
cocultivation was determined by immunostaining of immediate-early antigen. Although all strains established permissive infection in
HAEC to some degree (including lysis of individual infected cells)
(Fig. 2; see Fig. 4), quantitative analysis clearly distinguished endotheliotropic from nonendotheliotropic strains by the efficiency of
infection and by the ability to disseminate in the infected HAEC
cultures. All fibroblast-propagated strains clearly exhibited dramatically reduced cell-free efficiency of infection in HAEC compared
to efficiency of infection in HFFs (Table 1). None of these strains was
able to form infectious foci of more than three cells per focus (Fig.
3; Table 2) or to disseminate
within HAEC cultures (Fig. 2E). In contrast, all
HUVEC-propagated strains displayed higher relative efficiencies
of infection (Table 1). More importantly, both HUVEC-propagated
strains, TB40/E and VHL/E, were able to form infectious foci and
disseminate in HAEC cultures, as indicated by focus expansion values of
39 and 51 cells/focus, respectively (Fig. 3; Table 2). Following
cell-free infection of HAEC at an MOI of 10, endotheliotropic strains
induced complete lysis of infected HAEC cultures within 17 days (Fig.
2B), whereas nonendotheliotropic strains persisted in the infected HAEC
cultures for more than 32 days (data shown for TB40/F in Fig. 2E). The interstrain differences of virus dissemination and cytopathogenicity within HAEC cultures became particularly clear when the initial infectivity was equalized by a 100-fold-reduced MOI of the
EC-propagated strain (Fig. 2D versus 2E). As documented by sequential
phase-contrast micrographs of infected cultures, persistence of strain
TB40/F in HAEC cultures seemed to reflect a state of equilibrium
between lysis of the small fraction of infected cells and regeneration of uninfected cells (Fig. 4) rather than
persistence of the virus in individual infected cells.
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TABLE 2.
Comparison of cell-associated infection efficiency of
various HCMV strains in HFFs, HAEC, HUVEC, and placental
microvascular endothelial cells (HPEC-A1)
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FIG. 3.
Interstrain differences in cell-associated infectivity
of HCMV in HAEC as determined by FE assays. Detection of nuclear HCMV
immediate-early antigen by the immunoperoxidase technique 5 days after
cocultivation of few late-stage infected HFFs with abundand noninfected
HAEC is shown. (A and C) Fibroblast-propagated HCMV strain TB40/F. (B
and D) EC-propagated strain TB40/E. Panels C and D are magnifications
of the frames indicated in panels A and B, respectively.
Magnifications, ×40 (A and B) and ×170 (C and D).
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FIG. 4.
Sequential phase-contrast micrographs of HAEC cultures
at 21, 22, and 23 days p.i. (dpi) with fibroblast-propagated strain
TB40/F (MOI = 10). Identical frames of infected cultures were
photographed daily with a Zeiss Axiovert 135 microscope. For better
orientation, characteristic structures are indicated by arrows. Two
late-stage infected cells (characterized by nuclear inclusions) at 21 dpi are indicated by filled arrowheads. At 22 dpi these cells are lysed
and defects in the monolayer have occurred, which are filled by
noncytopathic cells at 23 dpi. Adjacent to these sites two new
late-stage infected cells appeared (open arrowheads) at 23 dpi.
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Comparison of HCMV infection in various EC types.
It is well
known that individual EC derived from different vascular beds
exhibit distinguishing characteristics. To compare responses of EC of
different vascular origins to HCMV infection, quantification of
cell-associated infectivity was performed in HUVEC and in a placental
microvascular cell line (HPEC-A1) (17), essentially as
described above for HAEC and HFFs. FE values for the various virus
strains in all four cell types were subsequently compared (Table 2),
and lytic end points were documented by phase-contrast micrographs. The
efficiency of infection in HAEC, HUVEC, and HPEC-A1 and the lytic
potentials of various HCMV strains (data not shown) were essentially
identical in each of these cell types. EC-propagated HCMV retained the
potential for focal dissemination in all EC types, whereas their
fibroblast-propagated counterparts were incapable of focal expansion in
HAEC, HUVEC, and HPEC-A1 (Table 2).
In summary, the data generated from these experiments imply that the
ultimate fate of HCMV-infected EC cultures (i.e., viral
persistence
versus lytic infection) is determined primarily by
properties inherent
in the virus itself, rather than by the vascular
bed of origin of the
EC. Specifically we have found that EC derived
from adult artery, fetal
vein, and placental microvasculature
all respond to infection with each
given strain of HCMV in an
essentially identical manner with
regard to efficiency of infection,
cytopathic alterations, and cell
lysis. Thus, although endothelia
populating different vascular
beds exhibit certain distinguishing
characteristics, their responses
to HCMV infection seem to be
quite similar. This conclusion
is further supported by studies
of Knight et al. (
9,
10), who demonstrated that patterns
of HCMV-mediated modulation
of endothelial HLA and adhesion molecule
expression were essentially
identical among EC derived from human
umbilical vein and matched
artery, human coronary artery, human
aorta, and human dermal
microvasculature. Although those studies
did not monitor cytopathic
change through to complete cell lysis,
efficiency of infection and
cytopathology were essentially identical
among all endothelial isolates
(
9,
10; W. J. Waldman, personal
communication).
Fish et al. (
6) have reported that inoculation of human
aortic EC with HCMV resulted in persistent, noncytopathic, and
nonlytic
infection. In contrast, our data clearly demonstrate
that certain HCMV
strains have the potential for extensive CPE
(cytomegaly and appearance
of inclusion bodies) and for complete
lysis of the infected HAEC
cultures. This apparent discrepancy
might be mainly explained by the
usage of EC-propagated strains
that have been shown to retain the cell
tropism of clinical isolates
(
22,
24). In contrast, isolate
Po used by Fish et al. has
been "passaged through HF [human
fibroblasts] and frozen below
passage 12 in liquid nitrogen"
(
5), and loss of natural EC
cytopathogenicity might have
occurred at that stage of fibroblast
propagation. Interestingly, we
also observed persistence of HCMV
in HAEC cultures when
fibroblast-propagated strains were used.
However, even with these
strains the occurrence of cytomegaly
with nuclear inclusions indicated
a CPE on a single-cell level
(Fig.
2E and
4). Moreover, on a
single-cell level, infection of
HAEC by these strains also resulted in
lytic infection (Fig.
4),
suggesting that HCMV persistence in HAEC
might possibly reflect
a balance between lysis of infected cells and
regeneration of
uninfected cells rather than persistence on a
single-cell level.
It may be questioned whether this might also explain
previous
reports by Fish et al. (
6) about persistence of
HCMV in human
aortic EC. In that work, the mitotic activity of infected
cells
had been assessed by judging their DNA content. However, this
method seems to be inappropriate for permissively infected cells
that
produce numerous viral particles containing viral DNA (
6).
In addition, viral immediate-early antigen expression in mitotic
cells
had been shown to demonstrate that infected cells are capable
of cell
division. However, this pattern could as well reflect
recent infection
of a cell which was already in the state of mitosis
at the time of
infection. In contrast, early or late viral proteins,
which should also
be detectable when mitotic activity of productively
infected cells is
assumed, had not been demonstrated in dividing
cells. Thus, based on
the primary data obtained, these findings
are not inconsistent with our
finding of lytic infection in a
fraction of cells when
fibroblast-propagated isolates TB40/F and
VHL/F were used. Clearly, it
cannot be excluded that other cells
in the population are not lytically
infected, and differences
in cells, culture conditions, and virus
strains might further
explain part of the discrepancies. Still, based
on the evidence
presented here, the assumption of a balance between
lysis of infected
cells and regeneration of uninfected cells would
provide a simple
explanation for persistence of fibroblast-adapted
strains in EC
cultures.
Our finding of cytopathic lytic infection of HAEC by HCMV has
significant implications for considerations regarding the pathogenesis
of HCMV infections. Release of infectious virus progeny from late-stage
infected HAEC could promote the hematogenous spread of HCMV throughout
the organism. More important for the development of organ disease,
lysis of infected HAEC was demonstrated here for the first time
on a
single-cell level. If such a CPE also occurred in vivo, it
would result
in the development of lesions in the EC monolayer,
followed by
thrombocyte aggregations, attraction of leukocytes,
and transmigration
of immune cells into parenchymal tissue (
4,
16). These
events might then promote transport of HCMV into
organ tissues by
transmigrating leukocytes (
3,
8,
14,
21,
23), vasculitic
reactions at sites of vascular injury
(
15,
26), and the
development of atherosclerotic lesions (
4,
16).
| |
ACKNOWLEDGMENTS |
The excellent technical assistance of Jutta Knapp and Heike Runge
is greatly appreciated. We thank P. Friedl for providing cell line
HPEC-A1.
This work was supported by the Bundesministerium für Bildung und
Forschung (Projektnummer 01 KI 9602) and by the Stiftung zur
Förderung und Erforschung von Ersatz- und
Ergänzungsmethoden zur Einschränkung von Tierversuchen.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Abt. Med.
Virologie, Universität Tübingen, Calwerstrasse 7/6, D-72076
Tübingen, Germany. Phone: 49 7071 2987459. Fax: 49 7071 295790. E-mail: christian.sinzger{at}med.uni-tuebingen.de.
| |
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Journal of Virology, August 2000, p. 7628-7635, Vol. 74, No. 16
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