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CONCANAVALIN A AND INFLUENZA VIRUS INFECTED CELLS
227
Interactions of Concanavalin A with the Membrane of Influenza
Virus Infected Cells and with Envelope Components of the Virus Particle
R . R O T T , H . B E C H T , H . - D . KLENK, a n d C . SCHOLTISSEK
Institut für Virologie, Justus Liebig-Universität, Gießen
( Z . Naturforsch. 27 b, 227—233 [1972] ; received December 12, 1971)
Dedicated,
to Prof.
WERNER SCHÄFER on the occasion
of his 60th
birthday
Treatment of host cells with Concanavalin A prevents the assembly or release of fowl plague
virus from chick fibroblasts and inhibits fusion of BHK cells by the paramyxovirus SV5. Metabolic
events of the host cells are not greatly impaired during the early phase of infection. There is evi
dence that the carbohydrate moiety of the Con A receptor of fowl plague virus is associated with
the viral neuraminidase.
Agglutination by Concanavalin A (Con A ) is one
Materials and Methods
of the manifestations of the alterations which the
membranes of the host cells undergo after they had
Virus, tissue cultures and inhibition assay
been infected with enveloped viruses. This pheno-
Fowl plague virus as a representative of influenza
viruses was grown in the allantoic cavity of 11-day
chick embryos and used for the infection of chick embryo
fibroblasts. After an adsorption period of 30 min. the
cultures were washed and 2 ml of Eagle's Minimal Essential Medium containing 200 //g of Concanavalin A
(Con A, purchased from Sigma) were added. At hourly
intervals post infection two dishes were removed from
the incubator, medium and cells were harvested and
assayed for hemagglutinin, neuraminidase, RNP-antigen and plaque forming units according to standard
procedures. Special treatments are described in results
or in the legends of the respective tables.
menon has been observed with a large number of
RNA
viruses and vaccinia virus in various
cell
systems, and it could never be observed with nonenveloped viruses
1-4
. Since parts of the cell mem-
branes altered during the budding process f o r m the
matrix of the viral envelopes, it was not surprising
to find suspensions of completed virus particles to
be agglutinable by Con A 2 ' 5 . This means that the
specific receptors for the phytagglutinin are exposed
at the surface of the infected cell and appear in the
viral envelope. Agglutinability of fowl plague infected
fibroblasts
occurs very early during the re-
plication cycle, even before hemagglutinin or infectious virus is released into the medium 1 . Exposure of Concanavalin A receptors seems to be among
the earliest changes demonstrable in an infected cell.
This observation prompted us to study the influence
of Con A on viral replication, particularly
on the synthesis of viral components and on viral
release.
Since it had been shown that removal
of
the
outer layer of the viral envelope by bromelin left a
spikeless particle which was not agglutinable
by
Con A any longer 5 , we tried in a further series of
experiments to determine more precisely whether the
specific receptor determinant is associated with hemagglutinin
or neuraminidase, the components
re-
moved by the bromelin treatment.
Requests for reprints should be sent to Dr. R. ROTT,
Institut für Virologie d. Justus-Liebig-Univ., D-6300
Gießen, Frankfurter Str. 87.
Agglutination of infected cells by Con A and inhibition
by viral components
Chide embryo fibroblasts infected with fowl plague
virus were washed 6 hours post infection, and the cell
layer was dispersed with EDTA as described before 2 .
0.1 ml of isolated hemagglutinin or neuraminidase in
at twofold dilution series was mixed with 0.1 ml of
40 ^g/ml of Con A, corresponding to approximately 4
minimal cell agglutinating units. After 10 min at room
temperature 0.2 ml of the cell suspension were added,
the reaction was continuously observed and the final
result scored after 10 minutes.
Preparation of hemagglutinin and neuraminidase
Hemagglutinin was obtained from virus concentrated
from allantoic fluid. The preparation was split with
Tween 80 (2.5mg/ml) and ether, and hemagglutinin
was isolated by adsorption to erythrocytes at 4 °C and
elution at 37 °C. The eluate was concentrated by pressure dialysis. Hemagglutinin and neuraminidase which
were maximally segregated were prepared from the
classical "viromicrosomes" 9 of infected chorioallantoic
membranes. After the allantoic fluid had been harvested
the membranes were removed from the eggs, washed in
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R. ROTT, H. BECHT, H.-D. KLENK, AND C. SCHOLTISSEK
228
PBS, homogenized as a 20% suspension, centrifuged
briefly to remove crude debris, and the "viromicrosomes" were finally spun down as described. The pellet
was resuspended in 0.02 M Tris/HCl buffer, pH 7.8,
containing 0.5 M KCl, homogenized with 0.5% of Triton X-100 for about 2 min and treated with V 2 Vol. of
peroxide-free ethyl ether. Treatment of the suspension
with the detergent and ether was done in an ice bath.
The aqueous phase was removed after centrifugation at
4000 rpm for 20 min and residual ether was blown off
with a stream of nitrogen. After a final centrifugation
step at pi 25, the supernatant was used for the precipitation test with Con A. Neuraminidase was prepared by
destroying the other virus components and most of the
cellular proteins with pronase 10.
Trials to precipitate hemagglutinin or neuraminidase
with Con A
5 0 ( « g / m l of Con A had been added.
This finding was not surprising, since it had been
Experiments on cell fusion
Inhibition of cell fusion was studied with the W3
strain of the parainfluenza virus SV5 grown in the
MDBK line of bovine kidney cells as described by
CHOPPIN 6 .
Influence of Con A on RNA and protein
synthesis
( 3 H)
Incorporation of
uridine (30 C/mM) or ( 3 H)
leucine (1 C/mM) into chick fibroplasts in Petri dishes
of 9 cm in diameter was measured according to SCHOLTISSEK u . Virus-specific RNA was distinguished from
newly synthesized cellular RNA by specific hybridization with a surplus of non-labelled viral plus- and
minus-strand R N A 1 2 . The activity of influenza RNAdependent RNA polymerase was measured in a cytoplasmic extract of infected cells 5 hours p.i. by incorporation of ( 3 H)GTP into virus minus-strand RNA in
the presence of cofactors as described previously 1S.
be
amounts
detected
of
in
hemagglutinating
the culture
128
128
64
2
<2
<2
Removal of
Con A
[hrs. p . i . ]
H A units
in m e d i u m
Cell associated
H A units
PFU/ml
1
2
3
4
5
6
without
Con A
< 2
< 2
< 2
< 2
< 2
< 2
128
12
6
3
< 2
< 2
< 2
1000
5-105
2-105
1.5 • 10 5
1 • 10 5
1 • 105
7.5 • 10 5
1.2-107
1*
2*
3*
4*
<
<
<
<
<
<
4
8
4
2
2
2
1 • 105
2-105
2.7 • 10 5
3.5 • lO 5
7.5 • 10 4
5 - 10 4
5*
6*
2
2
2
2
2
2
<
<
<
Table 2. Replication of FPV in the presence of Concanavalin A for different periods. Con A containing medium (50
jug/m\)
was removed at the time after infection indicated and
incubation was continued with normal medium until 8 hours
p. i. * = Incubation with normal medium was continued for
6 hours.
known f r o m previous experiments that virus particles are readily agglutinated by Con A . Absence of
viral activities in the culture medium could have
been due, therefore, to aggregate formation of released virus b y Con A . On the other hand, binding
of
Con A b y the altered surface of the infected
cells, which becomes manifest by the agglutinability
of such cells, could mediate a block in viral release.
A series of experiments was set up to decide between
these alternatives. Table 2 presents the results of exreplaced
The dose response curve (Table 1) shows that no
could
0
0.1
1
10
50
100
periments where the Con A-containing medium w as
Results
significant
HA-units
Table 1. Dose response of FPV release in the presence of
Concanavalin A .
The Tween/ether split-product from virions or the
hemagglutinin/neuraminidase mixture prepared from
"viromicrosomes" were mixed with equal amounts of
Con A (100 jug/ml) at room temperature and centrifuged after 30 min at pi 5. The supernatant was assayed for residual hemagglutinating and neuraminidase
activities. The pellet was assayed after ultrasonic dispersion.
Monolayers of baby hamster kidney (BHK 21-F)
cells 7 were propagated in reinforced Eagle's Medium 8
with 10% calf serum and 10% tryptose phosphate broth.
Monolayers in plastic Petri dishes (diameter 6 cm)
were inoculated with SV5 at a multiplicity of 10 PFU/
cell. After an adsorption period of 90 min 2 ml reinforced Eagle's Medium without calf serum and
tryptose phosphate broth were added.
A m o u n t o f Con A
in culture m e d i u m
Ug/ml]
medium
activity
when
by
normal
culture medium
at different
periods after infection. These data show that completion of
the 8 hours replication cycle of
FPV
under the usual conditions or a continued incuba-
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CONCANAVALIN A AND INFLUENZA VIRUS INFECTED CELLS
229
tion of another 6 hours after removal of Con A did
not liberate any virus into the medium.
than in controls, when the cell homogenates were
Even treatment of the monolayer f o r 2 hours with
1 0 0 / / g / m l of Con A before the cultures were inoculated with infectious allantoic fluid prevented the
appearance of any virus-specific material in the
medium after 8 hours of incubation (Table 3 ) .
and ether (equal volumes).
Con A
added
Cell associated
PFU/ml
H A units
+
+*
512
<2
64
5-107
1.4 • 10 4
7 • 10 5
Neuraminidase
units
5400
80
1360
HA-units
in m e d i u m
256
<2
<2
Table 3. Binding of Concanavalin A to uninfected cells.
Con A (50 jMg/ml) was added 2 hours prior to infection, the
cells were washed twice, infected and incubated as usual.
Cells were processed by freezing and thawing ( + , —) or by
ultrasonication ( + * ) .
Agglutinating titer o f
Con A solution
Con A
nonabsorbed
absorbed
sonicated or treated with Tween 8 0
without
20
16
20
20
20
20
20
3-104
5-104
1.2 • 105
1.5 • 10 5
1 • 10 5
7.5 • 10 4
7.5 • 10 4
400
530
580
620
520
580
560
96
96
96
96
96
96
96
256
3.5 • 10 7
3600
96
Con A added
1/16
1/2
Firm binding of Con A by normal cells could also
be demonstrated in absorption experiments. The reduced agglutination titers f o r FPV-infected cells in
Table 4 show clearly that a considerable amount of
Con A was absorbed by uninfected chick
fibroblasts
during the 2 hours incubation.
+
+
+
+
+
+
+
+
The unexpected result of the experiments presented in Table 2 and 3 was the lack of any demonstrable hemagglutinin after the cells had been broken b y the commonly used three cycles of freezing
and thawing. This finding, based solely on the conventional
technique
of
processing
infected
cells,
would have indicated that not only release of virus
particles but also synthesis of viral components was
RNPantigen
units
Table 5. Aggregation of cell associated activity by Concanavalin A . 50 jug/ml
Con A was added at the time indicated.
Cells were harvested 8 hours after infection and assayed after
ultrasonication for 15".
H o u r s after
infection
Table 4. Absorption of Concanavalin A by uninfected cells.
Approximately 10 7 chick fibroblasts were suspended in 1 ml
of PBS containing 100 /ig of Con A. After 2 hours at room
temperature the cells were spun down and the agglutinating
activity of the supernatant tested with FPV-infected cells.
Neuraminidase
units
[fig N A N A /
ml]
Addition
Cell associated
o f Con A
[hours p. i.] H A PFU/ml
units
0
1
2
3
4
5
6
(12.5mg/ml)
Cellassociated
H A units
Hemadsorption
<2
< 2
< 2
< 2
48
< 2
420
< 2
512
< 2
750
< 2
512
< 2
750
4
Table 6. Hemadsorption by chick fibroblasts infected with
fowl plague virus after treatment with Concanavalin A .
100 [Ag of Con A were added to the test plates immediately
after the adsorption period. The monolayers were washed twice
with PBS at hourly intervals and 2.5 ml of a 1% suspension
of chick erythrocytes were added. After 15 min at room temperature the plates were washed again five times and the degree of hemadsorption (H
+ + + + ) was scored microscopically.
blocked. However, presence of hemagglutinin and of
could
Aggregation of virus products and their firm at-
fluorescence
tachment to cell debris became obvious when Con A
RNP-antigen in cells incubated with Con A
be clearly demonstrated b y a brilliant
in ultraviolet light after staining of these cells with
was added at different periods post infection after
fluorescein-conjugated
virus synthesis had proceeded normally (Table 5 ) .
anti-hemagglutinin and anti-
RNP-serum. Hemagglutinin could be regained f r o m
Hemadsorption
Con A-treated cells, although in smaller quantities
treated with Con A furnished further evidence that
to infected cells which were pre-
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R. ROTT, H. BECHT, H.-D. KLENK, AND C. SCHOLTISSEK
230
virus-specific products had been synthesized
and
introduced into the cell membrane (Table 6 ) .
Microscopic
examination
of Con A-treated
InCon
fected A
After 2 4 hours the Con A-treated cell layer was
still adherent to the Petri dish. All cells had a granulated appearance and many cells had rounded and
contracted. The monolayers of infected control culincubated
without
Con A
were
totally
stroyed. However, the cells in the still
Con A-treated
monolayers
were
all
de-
adherent
stained
with
trypan blue, indicating severe cell damage b y the
infection. Uninfected cultures incubated in the presence of Con A had only few rounded and stained
cells.
Inhibition
of virus-induced
Concanavalin
cell fusion
Disintegrations per min • l O - 2
(3H)
( 3 H ) uridine
TCAleucine
RNA
extract
protein
0
0
6
6
6
6
15
15
15
15
23
23
23
23
780
860
270
570
555
1120
98
288
92
125
68
177
*
6150
6565
1720
4200
2230
3950
540
2360
668
1140
310
1150
83
533
mono-
layers
tures
Start o f
pulse
hrs. p . i .
by
A
Table 7 shows that the parainfluenza virus SV5
+
—
—
—
+
—
+
+
—
+
—
+
—
+
+
—
+
+
+
—
—
—
+
+
1110
1150
282
1240
305
515
121
715
45
224
104
537
*
*
212
Table 8. Effect of Con A on R N A - and protein metabolism of
uninfected and infected tissue cultures. 100 y/ml Con A was
added to 50% of the cultures immediately after infection. ( 3 H)
uridine or ( 3 H) leucine (1.25/^C/culture) were added at different times after infection. The pulse length was 1 hr. Noninfected control cultures were treated and worked up in
prallel. * = Monolayer completely destroyed.
causes in BHK 21-F cells extensive cell fusion. Giant
cell formation began about 10 hours after infection
plication cycle. RNA-synthesis itself seems not to be
and rapidly progressed to the formation by 2 4 hours
greatly influenced since the radioactivity in the tri-
of a single syncytium 7 . Con A had an inhibitory
chloroacetic
effect on cell fusion. Giant cell formation was com-
derivatives) parallels the radioactivity incorporated
acid-soluble
pool
(uridine
phosphate
into R N A .
Concanavalin A
added
amount
[hrs. p . i . ] [ / / g / d i s h ]
200
1.5
3
50
200
6
50
200
Control
0
8
10
11
14
Furthermore, the effect of Con A on the product-
24
[hrs. p . i . ]
ion
la
1
1
1
1
1
1
5
1
>100
-10 > 1 0 0
1
complete
fusion
pletely suppressed, if 2 0 0 jug Con A per dish were
added 1.5, 3 or 6 hours after infection. At a concentration of 5 0 jug per dish there is still a significant delay in giant cell formation.
of Con A on cell metabolism
viral RNA
influenza R N A
polymerase was examined
of influenza R N A polymerase in the presence of
10
Table 7. Inhibition of cell-fusion by Concanavalin A . a Nuclei
per cell. The number of nuclei per cell is used as a parameter
for cell fusion induced by SV5.
Eßect
of
5 hours after infection. As shown in Fig. 1 the yield
Con A is still about 6 0 % of that without lectin.
Since infected cells were still adherent to the Petri
dish 15 hours after infection, the synthesis of viral
R N A in these cells was examined. By specific hybridization with non-labelled viral plus- and minusstrand R N A it was found, that 15 hours after infection in Con A-treated cells less than \% of the newly
synthesized R N A (pulse with ( 3 H ) uridine f r o m 15
to 16 hours p.i.) was virus-specific. At 4 hours p.i.
virus-specific R N A is about 15% of the newly synthesized R N A
Inhibition
and on
influenza
synthesis
viral
12.
of cell agglutination
by components
of the
envelope
Hemagglutinin prepared by desintegrating FP\
As shown in Table 8 Con A has a stimulating ef-
viria with Twreen 8 0 and ether inhibited agglutina-
fect on the uptake of ( 3 H ) uridine and ( 3 H ) leucine
tion of FPV-infected fibroblasts by Con A. Aggluti-
into uninfected as well as into infected cells, even
nation gradually reappeared upon serial dilution of
6 hours post infection, a very late stage of the re-
the hemagglutinin (Table 9 ) .
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CONCANAVALIN A AND INFLUENZA VIRUS INFECTED CELLS
74
231
Since it is known that this "hemagglutinin" contains at least two virus-specific components, the true
hemagglutinating substance and viral neuraminidase, we tried to decide whether the Con A-specific
carbohydrate is attached to one of these structures
or to both. Since hemagglutinin is not available yet
in pure f o r m and the purification procedure f o r
isolated neuraminidase involves treatment with
pronase, another approach was chosen f o r this
question.
?o
5
Precipitation
of neuraminidase
by Con A
Con A was added to a mixture of hemagglutinin/
neuraminidase solubilized f r o m viromicrosomes with
0.5 M KCl and 0.5% Triton X - 1 0 0 . The phytagglutinin precipitated almost exclusively neuraminidase.
After centrifugation the supernatant was nearly de0
5
10
.
min
15
prived of enzymatic activity, but it had retained vir-
Fig. 1. Effect of Con A on the production of influenza R N A
polymerase. 5 infected tissue cultures received 100 y/ml
Con A immediately after infection, 5 infected cultures were
incubated without Con A . 5 hours p. i. a cytoplasmic fraction
(3.1 p g / m l protein) was prepared and tested for R N A polymerase activity by incubation at 32 ° C with ( 3 H) G T P plus
cofactors 13 . o — o = plus Con A ; • — • = without Con A .
Dilution
of hemagglutinin
( - l o g 2)
Cell agglutination
1
2
3
4
5
6
7
PBS
tually all of its hemagglutinating capacity
(Table
1 0 ) . The same experiment with a hemagglutinin prepared with Tween and ether f r o m viria had a somewhat different outcome;
hemagglutinating
a substantial amount
activity
was removed
from
supernatant in this case. When the complex
dissociated by readdition of a detergent
NP-40,
of
the
was
(Nonidet
1 % ) , hardly any hemagglutinin was pre-
cipitated. A still different result was obtained when
neuraminidase purified by treatment of viria or of
0
0
0
+
++ ++ ++ + +
CAM-extracts with pronase was used in the precipitation test. A considerable amount of enzyme was
not precipitated by Con A f r o m these preparations.
Table 9. Inhibition of Concanavalin A mediated agglutina
tion of FPV-infected cells by hemagglutinin. 0.1 ml of Con A
(40 « g / m l ) was mixed with 0.1 ml of diluted hemagglutinin
(30 000 H A units isolated from purified F P V by Tween/ether
treatment). After 10 min at room temperature 0.2 ml of
E D T A dispersed cells were added and the agglutination pattern read 15 min later.
T y p e o f viral c o m p o n e n t s
In each experiment total hemagglutinating and enzymatic activities could not be fully recovered f r o m
the pellets, because binding of Con A entrapped these
components so firmly within the precipitates that
they could hardly be dispersed.
Con A a d d e d
Sediment
1800
512
64
1400
1600
108
<
24
8
760
48
16
52
200
13
•
<
12
8
256
700
11
130
440
37
—
—
—
—
—
13
42
156
92
+
Tween-ether
treated F P V
+
Neuraminidase purified b y
pronase t r e a t m e n t
Neuraminidase [ u g N A N A / m l ]
Sediment
Supernatant
32
8
T r i t o n treated
V i r o m i c r o s o m e s in K C l
T w e e n - e t h e r treated F P V
in the presence o f N o n i d e t N P - 4 0
H A units
Supernatant
—
+
Table 10. Precipitation of envelope components of F P V by Concanavalin A . 1 mg/ml of Con A were mixed with an equal
volume of the virus preparations, left at room temperature for 30 min and centrifuged at a performance index of 7.5.
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R. ROTT, H. BECHT, H.-D. KLENK, AND C. SCHOLTISSEK
232
after treating the cell homogenate with Tween and
Discussion
The absence of any virus-specific activities in the
medium of FPV-infected cultures containing Con A
was not primarily due to precipitation and subsequent removal of liberated particles. The media
lacked virus because a block of viral release must
have occurred by binding of Con A to the cell membrane. Since virus production was also prevented by
treating
the
cultures
prior
to
infection,
a
firm
binding of Con A at the cell membrane must have
taken place. Attachment of the lectin to the membrane of normal cells could also be shown b y the
decrease in agglutination titers f o r infected
after normal
fibroblasts
cells
had been suspended in a
Con A solution. These findings are consistent with
reports f r o m other laboratories where it could be
shown that Con A is bound by normal as well as b y
transformed
cells14'15.
All
these results
indicate
that Con A receptors are accessible f o r the phytagglutinin at the surface of normal cells. The appropriate arrangement and exposure of the receptors at
the surface of an altered membrane seems to be the
essential condition f o r the agglutinability of transformed cells or of cells infected with an enveloped
virus.
After reaction of the receptors with Con A formation of a lattice structure could cause a considerable
loss of the membrane's flexibility and could impair
its normal functions which are probably necessary
f o r a normal synthesis of the components of the
viral envelope and f o r an undisturbed budding process. Rigidity of the cell membrane by such a network would explain the prolonged adhesion of the
monolayer to the Petri dish simulating the absence
of a fully developed CPE. The increased uptake of
( 3 H ) uridine implicates that the membrane becomes
more permeable, which is probably responsible f o r
the stimulation of U T P and of R N A labelling.
Such an alteration of the cell membrane seems
also to be responsible f o r the inhibitory effect of
Con A on cell fusion which is a c o m m o n feature of
paramyxoviruses and requires an intact viral envelope. It is conceivable that Con A impairs the formation of the envelope at the cell membrane b y a
mechanism outlined above. Alternatively, it could
be possible that the cell-fusing activity of the viral
envelope is inhibited by the mere adsorption
ether is due to a depressed synthesis of these components under the influence of Con A or merely a
result of the imperfectness of this method of solubilization. The relatively low degree of hemadsorption
in Con A-treated cultures would favour the first possibility.
The viral envelope components which had been
synthesized were firmly tied to the cell debris by
Con A after freezing and thawing of the cells. This
is consistent with
It cannot be fully assessed whether the relatively
low recovery of hemagglutinin and neuraminidase
observation
that
outer layer of the viral envelope. When hemagglutinin and neuraminidase were dissociated and were
individually in solution with a minimal degree of
complexing, Con A precipitated neuraminidase. This
underlines the suggestions derived f r o m acrylamide
gel analysis that neuraminidase is a glycoprotein
16
and it means that the Con A receptor substance is
mainly associated with neuraminidase and not with
hemagglutinin. Digestion with pronase had obviously
removed
part
neuraminidase
of
the
carbohydrate
from
the
molecule which indicates that the
cleavage site of the protease is closely adjacent to
the area where the carbohydrate moiety is attached.
Our results suggest that during the assembly of
the components of the viral envelope carbohydrates
are selectively incorporated into the viral protein
structures to f o r m the two major glycoproteins hemagglutinin and neuraminidase, each carrying
dif-
ferent carbohydrate moieties.
A final consideration is pertinent to the fact that
Con A is a bifunctional reagent which binds firmly
to neuraminidase via the carbohydrate moiety of
this glycoprotein and is capable of blocking viral
release. Comparable conditions are met in experiments with anti-neuraminidase antibodies which inhibit viral release 1 7 . Since Con A, a bifunctional
reagent which binds to neuraminidase and to receptors of the cell membrane without influencing the
enzyme's active site, is capable of eliciting the same
effect, the conclusion reached with monovalent antibodies is stressed that inhibition of virus release by
anti-neuraminidase antibodies is rather due to lattice
formation than to a block of the active site of the
neuraminidase molecule
of
Con A to the cell membrane.
our previous
Con A receptor substances are associated with the
18.
We gratefully acknowledge the excellent assistance
of
MICHAELA
ORLICH
and
BRIGITTE
PIONTEK.
The
work was supported by the Sonderforschungsbereich 47
(Virologie).
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SERUM HEPATITIS AND SEROPROPHYLAXIS
1
2
3
4
5
6
7
8
9
H. BECHT, R . ROTT, and H.-D. KLENK, Z . med. M i k r o b i o l .
u. Immunol. 1 5 6 , 3 0 5 [ 1 9 7 1 ] .
H. BECHT, R . ROTT, and H.-D. KLENK, J. gen. V i r o l o g y ,
14, 1 [ 1 9 7 2 ] .
J. M . ZARLING and S. S. TEVETHIA, V i r o l o g y 4 5 , 313
[1971].
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Serum Hepatitis and the Seroprophylaxis of Measles
A . P.
WATERSON
Department of V i r o l o g y , R o y a l Postgraduate M e d i c a l School, D u C a n e R o a d , L o n d o n , W . 12., E n g l a n d
(Z. Naturforsch. 27 b, 233—241 [1972] ; received January 20, 1972)
Dedicated,
to Prof.
WERNER SCHÄFER on the
occasion
of his
60th
birthday
T h e events leading to the recognition of serum hepatitis ( " h o m o l o g o u s serum j a u n d i c e " ) as a disease
entity are d e s c r i b e d and reasons given w h y s e r o p r o p h y l a x i s against measles played an important
role in this discovery. T h e i n j e c t i o n of human serum as a p r o p h y l a c t i c was practised on an increasing scale f r o m about 1920 to a b o u t 1950, by which time it had largely been superseded by
i m m u n o g l o b u l i n (gamma g l o b u l i n ) . A p a r t f r o m the transfusion of b l o o d and b l o o d products the
other m a j o r human to human transfer of material was vaccination against yellow fever in the years
1937 — 1 9 4 0 . T h e c o n s e q u e n c e s of this large scale interchange between human s u b j e c t s included the
dissemination of serum hepatitis virus, and the possibility of transfer of other viruses is discussed.
Serum hepatitis has recently become amenable to
laboratory study, in spite of the fact that the virus
which causes it has not yet been isolated 2 . Much
of the interest in the disease has centred around the
patients and staff of renal dialysis units 3 and those
involved in renal transplantation, but the treatment
of chronic renal failure is only one of a number of
situations involving operative treatment of the
patient and the transfusion of large volumes of
blood, either as repeated small transfusions or as a
large quantity given at once. Transplant surgery
and major cardiac survery are, like renal dialysis,
procedures which twenty years ago were performed
on relatively few patients, but have now become
routine measures practised widely on relatively large
numbers of patients, and they too have contributed
to the increase in the quantities of blood and plasma
transfused. There has also been an increasing range
of blood products, such as anti-haemophilic globu-
Requests for reprints should b e sent to Dr. A . P . WATERSON, Department of V i r o l o g y , R o y a l Postgraduate M e d i c a l
School, D u C a n e R o a d , London,
W. 12 ( E n g l a n d ) .
lin, cryoprecipitate, concentrated platelets and radioiodine-labelled fibrinogen, some of which are available as preparations pooled from several donors.
In addition, some of these situations involve either
artificial suppression of the immune response, as
after transplants, or a natural diminution in this
response, as in the uraemic patients on long-term
renal dialysis.
There has also been a steady increase in the
number of surgical operations, and in elaborate
diagnostic procedures such as cardiac catheterization and various radiological investigations, all
entailing at least some spillage of the patient's
blood and its contact with doctors and perhaps other
patients. The application of these techniques has of
course entailed an enormous increase in laboratory
investigations involving the handling of samples of
blood and serum. This increase in the scale of
laboratory investigation extends also to non-surgical
patients, for example to those undergoing intensive
therapy for leukaemia or chorion-carcinoma, such
therapy involving the combination of blood transfusion and immuno-suppression.
Unauthenticated
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