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*
Department of Microbiology and
Cancer Research Unit, Faculty of Medicine, The University of Newcastle, Newcastle, New South Wales, Australia; and
Department of Immunoregulation, Research Institute of Microbial Diseases, Osaka University, Suita, Osaka, Japan
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DAF protects cells from complement-mediated lysis by blocking the C3 and C5 convertases of the classical and alternate pathways (1). DAF prevents formation of cleavage fragments C3a and C5a and furthermore inhibits the amplification of the C cascade on the surface of host cells. Purified soluble DAF can inhibit complement activation in vitro and in vivo (8). However, the anticomplement activity of purified DAF is substantially increased when it is reincorporated in the cell membrane (8, 9), suggesting that membrane anchoring of DAF induces favorable changes in its functional conformation.
Recently, DAF has additionally been shown to interact with a number of cell surface molecules, and also with human intestinal pathogens. DAF has been proposed as a cellular ligand of CD97 (10), an activation-induced Ag on leukocytes, and has been shown to share a spatial association with coexpressed intercellular adhesion molecule-1 (11). Escherichia coli-bearing adhesins of the Dr family bind to DAF SCR3 (12), and an increasing number of human enteroviruses are being shown to bind to different DAF epitopes. Coxsackievirus A21 binds to DAF SCR1 (11), while Coxsackievirus B3 and a number of echoviruses bind to epitopes located in DAF SCR2 and SCR3 (13, 14, 15, 16). However, the role of DAF other than as an initial attachment receptor in the infection mechanism of these pathogens is unclear and is currently an area of much investigation. Interestingly, many of these viruses can infect the cells of many human tissues that have been reported to be surrounded by fluids containing soluble forms of DAF (17).
In this report we investigated whether a potential cause for the reduced antienteroviral activity of purified soluble DAF compared with the membrane-bound DAF was due to a reduced accessibility to the functional third SCR. Competitive Ab binding studies revealed that Ab binding to DAF SCRs 1 and 3 of purified non- membrane-bound DAF can be substantially increased by prior exposure to mAbs against SCRs 3 and 1, respectively. An unexpected finding of this study was that pretreatment of membrane-bound DAF with mAbs to SCRs 1 and 3 dramatically enhanced the respective cellular attachment and infectivity of the human enteroviruses echovirus 7 (E7), which binds SCR3, and Coxsackievirus A21 (CAV21), which binds SCR1. This finding is the first report of an antiviral receptor Ab enhancement of viral infectivity that does not involve Fc-receptor interactions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CHO-DAF cells were obtained from Dr. Douglas Lublin, Department of Pathology, Washington School of Medicine, St. Louis, MO (7). HeLa-B cells, rhabdomyosarcoma (RD) cells, echovirus 7 (Wallace), and Coxsackievirus A21 (Kuy Kendall) were obtained from Dr. Margery Kennett, Entero-respiratory Laboratory, Fairfield Hospital, Melbourne, Australia. Anti-DAF mAbs IA10 (IgG2a), VIIIA7 (IgG1), and IIH6 (IgG1) were prepared as described (18); mAb IH4 (IgG1) (7) was supplied by Dr. Bruce Loveland, Austin Research Institute, Heidelberg, Australia, and mAb 1C6 (19) was supplied by Dr. T. Fujita, Department of Biochemistry, Fukushima Medical College, Fukushima, Japan. The anti PTA-1 mAb (A1; IgG1) was supplied by Dr. G. F. Burns and prepared as described (20). mAb CLB-CD97L/1 (IgG1) (10) was supplied by Dr. J. Hamann, Central Laboratory of the Netherlands Red Cross Blood Transfusion service, University of Amsterdam, Amsterdam, The Netherlands. All mAbs used in this study were purified from ascites fluids.
F(ab')2 preparation
F(ab')2 Ab fragments were prepared from whole mAb VIIIA7 (IgG1) by digestion with resin immobilized-ficin and protein G gel chromatography according to the manufacturer’s protocol (Immunopure Kit no. 44880; Pierce, Rockford, IL).
Virus binding assays
CHO-DAF or RD cell monolayers in 24-well tissue culture plates were first incubated for 1 h at 22°C with mAbs A1, IA10, VIIIA7, IH4, and IIH6 (20 µg/ml) in DMEM containing 1% BSA (DMEM-BSA) and then washed and incubated with purified 35S-labeled CAV21 or E7 (4 x 105 cpm) for the same period. Following four washes with PBS, the cell monolayers were dissolved in 200 µl of 0.2 M NaOH-1% SDS and the amount of labeled virus that was bound was measured by liquid scintillation counting. Results are expressed as the means of triplicate wells + SD.
Virus infectivity assays
RD cell monolayers in 96-well plates were incubated with 50 µl of a control mAb and mAbs to each DAF SCR (20 µg/ml) diluted in DMEM for 1 h at 37°C. Cells were then challenged with 10 to 104 50% tissue culture infectious doses (TCID50)/well of either E7 or CAV21 in DMEM containing 1.0% FCS (DMEM-FCS) and incubated at 37°C for 48 h. To quantitate cell survival, monolayers were incubated with a crystal violet/methanol solution, washed with distilled H2O, and the plates were read on a multiscan ELISA plate reader (Flow Laboratories, McLean, VA) at a wavelength of 540 nm. Results are expressed as mean percentage cell lysis relative to uninfected cell monolayers.
DAF ELISA
Wells of a microtiter plate were coated with 100 µl of mAb IIH6 (4.5 µg/ml) for 4 h at 37°C, washed, and incubated with 100 µl of either purified DAF (0.5 µg/ml) or supernatant from DAF-expressing HeLa-B cells incubated with phosphatidylinositol-specific phospholipase C (1.0 U/106 cells) for 1 h at 37°C. The purified DAF was supplied by Dr. Tomita, Showa University, Showa, Japan (21). The plate was washed three times with PBS containing 0.05% Tween-20 (PBS-Tween) and incubated with 0.1 ml of anti-DAF mAbs (10 µg/ml) for 1 h at 37°C. The plate was washed as before and incubated with 100 µl of biotinylated-IH4 (1 µg/ml) for 30 min at 37°C. Following three washes with PBS-Tween, 0.1 ml of a 1:1000 dilution of avidin-horseradish peroxidase conjugate (Amersham Life Science, Amersham, U.K.) was added to each well and the plate was incubated for 30 min at 37°C. The plate was washed three times more, 100 µl of tetramethylbenzidine solution was added to each well, and the plate was incubated for 15 min at 37°C. The reaction was stopped by the addition of 100 µl of 2 M H2SO4, and the absorbance was measured at 450 nm.
Flow cytometry
RD cells (5 x 105) were incubated with the appropriate mAbs (10 µg/ml) diluted in PBS containing 1% BSA (PBS-BSA) at 0°C for 30 min, after which the cells were washed with 5.0 ml of PBS-BSA. The cells were then pelleted at 1000 x g for 5 min and resuspended in 100 µl of fluorescein isothiocyanate-conjugated goat anti-mouse Ig G (heavy plus light chains) (Silenus, Melbourne, Australia) diluted in PBS-BSA. Following incubation at 0°C for 30 min, the cells were washed and pelleted as above, resuspended in PBS-BSA, and analyzed with a FACStar analyzer (Becton Dickinson, Sydney, Australia). For the competitive anti-DAF mAb binding assays, RD or CHO-DAF cells (5 x 105) were preincubated with the appropriate anti-DAF mAbs (10 µg/ml) for 30 min at 0°C, washed with PBS, then exposed to biotinylated mAbs IA10 or IH4 (1 µg/ml) for a further 30 min at 0°C. Cells were then washed with PBS and incubated with phycoerythrin-conjugated streptavidin (Sigma Chemical Co., St. Louis, MO) for 30 min at 0°C, washed with PBS, and analyzed as above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Competitive mAb binding was used to examine the accessibility of
mAbs directed against individual SCRs of both membrane-bound and
soluble DAF. We used biotinylated mAbs IA10 and IH4 against DAF SCR1 (a
nonfunctional SCR) and DAF SCR3 (a functional SCR), respectively, as
our detecting Abs. Ab blockade by mAb IA10 does not block DAF function,
while mAb IH4 totally abolishes DAF (7). Flow cytometric analysis
revealed similar levels of binding of all anti-DAF mAbs to the
surface of RD cells, except mAb IA10 (SCR1), which bound to a
significantly higher level (Table I
).
Subsequent flow cytometric studies revealed a considerable degree of
binding of mAb IA10 (10 µg/ml) to the surface of non-DAF-transfected
COS and CHO cells (e.g., mean intensity fluorescence of mAb IA10 and
mAb IH4 binding to mock-transfected COS cells of 125.02 and 7.51,
respectively; mean intensity fluorescence of mAb IA10 and mAb IH4
binding to DAF-transfected COS cells of 303.1 and 199.56,
respectively). This Ab also did not immunoprecipitate DAF-specific
proteins from biotinylated COS cells (11) and did not show increased
binding to purified DAF (Fig. 2). Therefore, nonspecific binding seen
in RD cells may account for the increased binding levels of this mAb
compared with other anti-DAF mAbs observed in this study. The
binding of biotinylated anti-DAF mAbs to membrane-bound DAF on the
surface of RD cells was quantitated by flow cytometry. RD cells (5
x 105) were preincubated with the panel of
anti-DAF mAbs (10 µg/ml) before incubation with either
biotinylated IA10 or IH4 (5 µg/ml) and phycoerythrin-conjugated
streptavidin. The data in Figure 1A indicate that the binding
of mAb IA10 was not significantly affected by the prior binding of any
of the panel of mAbs excluding mAb CLB-L1 (SCR1) and itself, while the
binding of IH4 was only totally blocked by mAb IC6 (SCR3) and itself
(Fig. 1B). The capacity of VIIIA7 to partially block
IH4 binding may be explained by the finding that its attachment to SCR2
is influenced by epitopes located in SCR3 (7). The slight inhibitory
effect on mAb IH4 binding exerted by mAb IA10 may be due to nonspecific
steric hindrance created as a result of its increased binding to RD
cells relative to the other anti-DAF mAbs (Table I) when used at a
concentration of 10 µg/ml. Similar results were obtained when CHO
cells stably expressing human DAF (7) were employed (data not
shown).
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A show that in this
environment, preincubation with mAbs to DAF SCRs 2 and 3 significantly
increased the binding of mAb IA10. Conversely, preincubation with the
anti-DAF SCR1 mAbs IA10 and CLB-CD97L/1 significantly increased the
binding of the anti-DAF SCR3 mAb IH4 (Fig. 2B).
In contrast to the binding data to membrane-bound DAF (Fig. 1B), mAb VIIIA7 slightly increased and mAb IC6 failed
to completely block IH4 binding (Fig. 2B). An almost
identical pattern of results was observed when DAF cleaved from the
surface of HeLa cells by phosphatidylinositol-specific phospholipase
treatment was captured onto the solid phase (data not shown). As the
purified soluble DAF used in this experiment was immobilized to the
solid phase by Ab capture (anti-SCR4), a possible indirect effect
exerted by this mAb either alone or in combination with the pretreating
mAb on binding of the appropriate biotinylated mAb cannot be
disregarded. Ab binding to membrane-bound DAF enhances Coxsackievirus A21 (CAV21) and Echovirus 7 (E7) cell binding and lytic infection
Next we investigated whether anti-DAF mAb binding to surface-expressed DAF could influence the attachment of other DAF-binding ligands such as the human enteroviruses, CAV21 and E7. Echovirus 7 binds to DAF SCR3 (16, 22), and we have recently shown that CAV21 binds to DAF SCR1 (11). However, despite expressing DAF on their cell surfaces, RD (a cell line commonly used for the primary isolation of human enteroviruses) and CHO-DAF cells bind relatively low levels of radiolabeled CAV21 and E7, a finding that may account for their lack of viral susceptibility.
To determine whether the low level of CAV21 and E7 binding was a
direct result of low DAF surface expression, flow cytometric analysis
was used to assess the relative levels of DAF expression on the surface
of RD and CHO-DAF to that of the highly permissive HeLa-B cell line
(Fig. 3A). The
fluorescence histograms indicate that the permissive HeLa-B cells
expressed significantly higher levels of DAF than either RD or CHO-DAF
cells.
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B).
However, mAbs recognizing DAF SCRs 2, 3, and 4 increased CAV21 binding
by between 6- to 15-fold on CHO-DAF cells and 3- to 7-fold on RD cells
(Fig. 3B). As expected for specific binding to DAF,
anti-DAF SCR3 mAb reduced the binding of E7 to both RD and CHO-DAF
cells. However, preincubation of both RD and CHO-DAF cells with an
anti-DAF SCR1 mAb increased E7 binding by approximately 5-fold,
while mAbs directed against DAF SCRs 2 and 4 had minimal effect on
binding (Fig. 3C). These results paralleled the
enhanced Ab binding of the biotinylated anti-DAF mAbs to SCR1 and
SCR3 to solid phase immobilized DAF preincubated with mAbs to DAF SCR3
and SCR1, respectively (Fig. 2).
The next step in the investigation was to determine whether Ab-induced
enhancement of viral binding increased the susceptibility of RD cells
to lytic infection by either E7 or CAV21. Confluent monolayers RD cells
in 96-well microtiter plates were preincubated with each of the
anti-DAF mAbs and challenged with CAV21 or E7. Viral infection was
allowed to proceed for 2 days at 37°C. The cell monolayers were then
assayed for cell survival. The data (Fig. 4A) indicated that RD
cells were rendered highly susceptible to CAV21 lytic infection by
pretreatment with the anti-DAF SCR2 and SCR3 mAbs. Conversely,
E7-induced cell lysis of the RD cells was increased dramatically
following monolayer pretreatment with a mAb to DAF SCR1 (Fig. 4A). The enhancement of E7 and CAV21 infectivity by
the anti-DAF SCR1 and SCR3 mAbs, respectively, was shown to occur
in a dose-dependent manner (Fig. 4B). Pretreatment of
RD cells with the anti-SCR1 mAb at a concentration as low as 10
ng/ml significantly increased cell susceptibility to E7-induced lytic
infection, while CAV21-mediated RD cell lysis was enhanced by an
anti-SCR3 mAb, limiting at a concentration of 100 ng/ml (Fig. 4B).
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It was important to establish that enhancement of viral binding and infectivity induced by the anti-DAF mAbs was the direct result of changes to the receptor itself, and was not caused by a phenomenon analogous to antiviral Ab-dependent enhancement of viral infectivity (23). Ab-dependent enhancement of viral infectivity occurs independent of the virus-cell receptor interaction and has been shown to increase the susceptibility of many cells to viral infection (e.g., HIV (23), dengue virus (24), foot and mouth disease virus (25)). In this phenomenon, cell infectivity is increased when non-neutralizing antiviral Ab binds to the virus and the complex is in turn bound by the FcR of the target cell, independent of its natural viral attachment receptor.
This was shown to be the case by four parameters: 1) CHO cells lack
FcRs (25) and by indirect immunofluorescence analyzed by flow cytometry
we were unable to identify any FcRs on the RD cells (data not shown);
2) a blocking mAb to FcRII had no effect on CAV21 infectivity of RD
cells and, in particular, did not influence the enhancement of
infectivity induced by the anti-DAF SCR3 mAb (data not shown); 3)
F(ab')2 fragments of mAb VIIIA7 enhanced comparable
levels of CAV21 cell lysis to that induced by whole mAbs VIIIA7 and IH4
(data not shown); 4) the increased infectivity and lysis of E7 on RD
cells treated with anti-DAF SCR1 mAb was completely inhibited by
cotreatment of the cells with anti-DAF SCR3 mAb, which blocks
specific viral attachment to this receptor (Fig. 4B).
Conversely, the enhanced infectivity of CAV21 induced by the
anti-DAF SCR3 mAb was abolished by the coincubation with the
anti-DAF SCR1 mAb that blocks binding of this virus to DAF (Fig. 4B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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20–25 nm) is
significantly greater than of an Ab molecule binding region, we suggest
that these viruses were able to test more rigorously the spatial
accessibility of different DAF epitopes. It is possible that cleavage
of the glycophosphosphatidylinositol linkage of membrane-bound DAF and
its subsequent attachment to a solid phase induces further
rearrangement such that SCR3 (or at least the epitope bound by mAb IH4)
becomes cryptic. Consequently, in the solid phase assay the postulated
cryptic epitope was exposed by treatment of the bound DAF with a mAb to
SCR1 of DAF, and this indicates that an Ab-mediated change may expose
the virus and Ab binding site on SCR3. This apparent increased
accessibility to the functional third DAF SCR following Ab interactions
with the nonfunctional SCR1 suggests a reduced spatial accessibility to
DAF SCR3 of purified soluble DAF compared with membrane-bound DAF.
Soluble DAF, such as that found in plasma and urine (17), may also be
in a configuration similar to that analyzed in the solid phase. If this
can be shown to be the case, our findings carry considerable
implications toward understanding the reported functional differences
between soluble and membrane-bound DAF (8, 9). In this regard, we have
found that DAF on the surface of untreated RD cells permits a degree of
E7 binding and cell entry (Figs. 3 and 4), whereas in preliminary
studies we have been totally unable to inhibit cell infection by E7
with soluble DAF (data not shown). The findings generated from this study not only provide insights into DAF structure but also impact in the area of clinical diagnostic virology. Their potential advantages are in the forms of 1) increased sensitivity for enteroviral-induced cytopathology testing and 2) an alternate approach to primary virus identification by monitoring differences in viral growth rates following antireceptor Ab-mediated changes in receptor structure.
The data presented here were obtained using an in vitro model; could this phenomenon occur in vivo? The prospect of anti-DAF Ab inducing changes in DAF structure within the body is unlikely. More probable is the ability of DAF-ligand interactions to enhance enterovirus binding. Thus, interactions between CD97, recently identified as a ligand for DAF or intercellular adhesion molecule-1 and membrane-bound DAF may facilitate enhanced usage of DAF as a functional enterovirus receptor. The exact CD97 binding domain on DAF has as yet not been identified, but preliminary evidence indicates that there may be multiple binding epitopes (10). It can also be speculated that binding of many enteric pathogens to DAF may have a direct regulatory effect on DAF receptor usage. For example, binding of E. coli-bearing adhesins of the Dr family to DAF SCR3 (13) may be sufficient to modulate DAF usage by a SCR1 binding virus such as CAV21 (11). Interestingly, in preliminary investigations, preincubation of CHO-DAF cells with either unlabeled CAV21 or E7 facilitated an increased level of binding of radiolabeled E7 and CAV21, respectively. Whether such Ab-mediated enhancement of enterovirus binding to DAF occurs by a mechanism similar to that reported for activating anti-integrin Abs (26) awaits further study.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Darren Shafren, Department of Microbiology, Faculty of Medicine, The University of Newcastle, Newcastle, New South Wales 2300, Australia. E-mail address:
3 Abbreviations used in this paper: DAF, decay-accelerating factor; SCR, short consensus repeats; RD, rhabdomyosarcoma; FcR, Fc receptor.
Received for publication June 23, 1997. Accepted for publication November 5, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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