The interaction between the malaria parasite and the red cell membrane


Yuthavong, Y.

Southeast Asian Journal of Tropical Medicine and Public Health 17(4): 635-641

1986


The malaria parasite intimately interacts with the host red cell membrane throughout the cycle of invasion and intracellular development. Direct interaction between the merozoite surface and the red cell membrane involves specific binding between the surface components of both cells, which leads to the subsequent endocytotic process still incompletely understood. Intracellular development of the parasite is accompanied by various changes in the structure and function of red cell membrane components. Some changes may benefit parasite survival while others trigger host immune response. An understanding of both the direct interaction between the surface components of the parasite and the red cell during invasion, and the subsequent changes in the red cell membrane following invasion, should lead to better ways of controlling malaria.

THE
INTERACTION
BETWEEN
THE
MALARIA
PARASITE
AND
THE
RED
CELL
MEMBRANE
YONGYUTH
YUTHAVONG
Department
of
Biochemistry,
Faculty
of
Science,
Mahidol
University,
Bangkok
10400,
Thailand.
INTRODUCTION
This
paper
examines
in
brief
the
interac-
tion
between
the
malaria
parasite
and
the
red
cell
membrane,
both
during
invasion
and
afterwards.
The
interaction
during
invasion
involves
the
specific
recognition
process
between
the
parasite
and
red
cell
surface,
leading
to
endocytosis-like
internalisation
of
the
former.
The
post-invasion
interaction
is
defined
as
that
leading
to
modifications
of
the
host
red
cell
membrane
in
both
structure
and
function,
some
of
which
may
be
of
benefit
to
parasite
survival
while
others
may
serve
as
signal
for
destruction
by
the
host.
The
molecular
architecture
of
the
red
cell
membrane
is
now
known
in
considerable
detail
(see
Schreier,
1985).
The
integral
membrane
proteins
spanning
both
sides
of
the
membrane
proteins
include
band
3
and
glycophorins.
Band
3
is
the
major
integral
protein,
and
probably
the
major
component
of
intramembrane
particles.
It
is
linked
with
spectrin,
the
major
membrane
skeletal
protein,
through
another
protein
ankyrin
(band
2.1).
The
glycophorins
(A,
B
and
C),
of
which
60%
by
weight
is
carbohydrate,
are
a
group
of
proteins
rich
in
sialic
acid
exten-
ding
beyond
the
membrane
surface.
Glyco-
phorins
are
linked
with
spectrin
through
the
protein
4.1.
The
bulk
of
the
membrane
skeleton,
underlying
the
inner
membrane,
is
a
network
of
spectrin
and
actin,
also
linked
Presented
at
the
Seminar
on
Recent
advances
in
Tropical
Medicine
Research,
24-28
February
1986,
in
commemoration
of
the
25th
Anniversary
of
the
establishment
of
the
Faculty
of
Tropical
Medicine,
Mahidol
University,
Bangkok,
Thailand.
via
protein
4.1.
The
interactions
among
these
membrane
proteins,
and
also
between
these
proteins
and
the
lipid
components,
are
important
in
determining
the
various
red
cell
membrane
functions.
These
interac-
tions,
as
well
as
interaction
of
individual
components
with
the
parasite
surface
must
play
an
important
role
in
parasite
invasion.
In
contrast
to
existing
knowledge
on
the
red
cell
membrane,
very
little
is
known
about
the
merozoite
membrane
and
other
parasite
components
which
take
part
in
the
invasion
process,
and
less
still
is
known
about
the
plasma
membrane
of
the
intracellular
parasite.
The
free
merozoite
has
a
plasma
membrane
with
a
glycoprotein
surface
coat,
and
two
underlying
pellicular
membranes
(Aikawa
and
Seed,
1980).
The
merozoite
surface
compo-
nents
which
may
play
a
part
in
the
invasion
and
subsequent
interaction
with
the
red
cell
membrane
include
glycophorin-binding
pro-
teins
(Perkins,
1984).
A
high
molecular-
weight
antigen
and
its
family
of
fragments
located
on
'the
merozoite
surface,
found
in
many
species
of
the
malaria
parasites
(P.yoelii,
MW
230,000;
P.
falciparum,
MW
195,000;
Holder
and
Freeman,
1984),
are
associated
with
protective
immunity,
but
their
role
in
the
interaction
between
the
merozoite
and
the
red
cell
surface
is
unclear.
A
number
of
other
protective
antigens
on
the
merozoite
surface
with
poorly
known
function
have
also
been
identified
(Anders,
1985;
Newbold,
1984).
INTERACTION
DURING
INVASION
The
invasion
of
the
red
cell
by
the
merozoite
follows
a
series
of
steps
involving
membrane
Vol.
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December
1986
635
SOUTHEAST
ASIAN
J.
TROP.
MED.
PUB.
HLTH.
processes
(Miller,
1977;
Aikawa
and
Seed,
1980;
Breuer,
1985).
Adherence
to
the
red
cell
can
occur
on
any
part
of
the
merozoite.
When
the
apical
end
of
the
merozoite
is
orien-
tated
to
red
cell
surface,
there
is
widespread
deformation
of
the
red
cell
and
a
junction
is
formed
at
the
contact
point.
The
merozoite
then
enters
into
the
endocytic
invagination
of
the
red
cell,
with
the
junction
at
the
orifice
moving
parallel
to
the
long
axis
of
the
mero-
zoite.
After
the
merozoite
is
completely
engulfed,
the
red
cell
membrane
fuses
together
sealing
off
the
vacuolar
membrane.
The
adherence
between
the
merozoite
and
the
red
cell
results
from
the
binding
between
the
surface
components
of
both
partners.
The
host
specificity
of
the
process
(Miller,
1977)
indicates
the
presence
of
specific
mole-
cules
involved.
Specific
molecules
may
also
be
involved
in
the
subsequent
processes
of
junction
fromation
and
parasite
entry.
The
junction
is
formed
through
clustering
of
in-
tramembrane
particles
on
the
P(protoplasmic)
face
of
the
erythrocyte
membrane
while
the
vacuolar
membrane
was
mainly
devoid
of
the
intramembrane
particles
(Aikawa
et
al.,1981).
Characterization
of
surface
molecules
in-
volved
in
the
invasion
process
can
be
made
by
identifying
genetically
variant
red
cells
which
are
less
susceptible
to
invasion
than
normal,
and
studying
the
surface
determinants
in-
volved.
Inhibition
of
invasion
following
treatment
of
red
cells
with
enzymes
which
degrade
surface
components
selectively,
or
with
antibodies
specific
to
certain
surface
components,
provides
valuable
clues.
In
both
of
these
approaches
uncertainty
may
be
creat-
ed
by
the
presence
of
a
secondary
effect
exerted
by
the
variant
or
modified
components
which
may
not
be
directly
involved
in
the
invasion.
Another
approach
is
to
study
the
inhibitory
effect
of
added
selected
components
isolated
from
the
red
cell
membrane
on
the
invasion
process.
In
this
case,
it
is
important
to
avoid
the
possibility
that
the
added
components
may
exert
an
adverse
effect
on
the
development
and
viability
of
the
merozoite.
The
red
cell
surface
components
involved
in
invasion
by
P.
knowlesi,
and
probably
also
P.
vivax,
have
been
shown
to
be
associated
with
Duffy
(Fy)
blood
group
determinants
(Miller
et
a1.,
1975).
Fy
negative
red
cells
are
resistant
to
P.
knowlesi
invasion
in
vitro,
apparently
due
to
failure
of
junction
formation
(Miller
et
al.,
1979).
Two
antigens
Fya
and
Fy
b
are
respon-
sible
for
the
phenotypic
expression
of
the
Fy
blood
groups,
and
anti-Fya
and
anti-Fy
b
sera
are
able
to
block
invasion
of
Fy
(a+b
-
)
and
Fy
(a
-
b+)
red
cells
respectively.
Invasion
of
Fy
(a+b+)
erythrocytes
is
blocked
by
treatment
of
the
red
cells
with
chymotrypsin.
The
Fya
antigen
has
been
characterized
as
a
35,000-43,
000
molecular-weight
protein
degradable
by
chymotrypsin
(Hadley
et
al.,
1984).
Athough
the
Fy
antigens
are
associated
with
parasite
invasion,
their
absence
does
not
abolish
all
latent
invasion
susceptibility
:
treatment
of
Fy
negative
red
cells
with
trypsin
or
neurami-
nidase
renders
the
originally
refractory
cells
susceptible
to
invasion.
The
Fy
antigens
therefore
play
an
important
role,
though
not
an
exclusive
one,
in
determining
the
course
of
interaction
between
the
red
cell
and
the
parasite
leading
to
invasion.
Reduced
invasion
of
P.
faleiparm
in
red
cells
devoid
of,
or
defective
in,
certain
blood
group
antigens
(Miller
et
al.,
1977;
Pasvol
et
al.,
1982)
pointed
to
the
possible
role
of
glycophorins
as
a
possible
specific
determinant
of
interaction
leading
to
invasion.
En (a
-
)
red
cells
lacking
in
glycophorin
A,
Tn
red
cells
with
underglycosylated
glycophorin
A,
and
S
-
s
-
U
-
red
cells
deficient
in
glycophorin
B,
all
showed
partial
resistance
to
invasion.
Invasion
of
normal
red
cells
can
also
be
inhi-
bited
after
treatment
with
enzymes
(trypsin
or
neuraminidase,
but
not
chymotrypsin)
which
cleave
glycophorin
A.
More
direct
evidence
was
obtained
from
the
observation
that
glycophorin
A
or
B
or
Fab
fragments
of
636
Vol.
17
No.
4
December
1986
MALARIA
PARASITE
AND
RELL
CELL
MEMBRANE
antibodies
to
glycophorin
A
added
to
the
culture
could
effectively
inhibit
merozoite
in-
vasion
(Perkins,
1981).
The
merozoite
surface
was
shown
to
have
glycophorin-binding
proteins
of
molecular
weights
155,000
and
130,000,
the
antibodies
to
which
could
effec-
tively
inhibit
the
invasion
(Perkins,
1984).
The
gene
for
a
glycophorin-binding
protein
has
been
cloned,
and
was
shown
to
code
for
tandem
repeats
of
50
amino
acids
in
a
sequence
with
alternate
hydrophobic
and
hydrophilic
blocks
(Ravetch
et
al.,
1985).
Although
these
results
indicate
a
major
role
for
glycophorins
in
specific
interaction
with
the
merozoite
which
triggers
invasion,
the
mode
of
this
interaction
is
still
unclear.
Since
these
proteins
carry
a
major
portion
of
surface
sialic
acid
it
might
be
expected
that
the
binding
domain
should
carry
a
high
negative
charge
density.
It
should
be
noted
that
a
number
of
macromolecules
bearing
negative
charge
could
also
compete
with
the
merozoite-red
cell
interaction
(Friedman,
1983).
On
the
other
hand,
free
sialic
acid
and
glycoconjugates
carrying
terminal
sialic
acid
residues
fail
to
inhibit
invasion
(Deal
and
Lee,
1981;
Breuer
et
al.,
1983).
It
was,
furthermore,
shown
that
up
to
40%
of
sialic
acid
can
be
removed
from
the
red
cell
surface
by
neuraminidase
or
trypsin
before
inhibition
of
invasion
was
observed
(Olson,
1984),
and
that
desialated
glycophorin
could
inhibit
invasion
to
a
comparable
extent
as
intact
glycophorin
(Breuer
et
al.,
1983).
It
is
possible
that
more
than
one
step
is
involved
in
the
binding
process,
the
exposed
negatively
charged
domain
providing
initial
but
rather
weak
binding
site,
while
the
internal
domain
provides
the
more
stable
subsequent
attach-
ment
site
for
the
merozoite.
Recent
work
has
furthermore
pointed
to
the
role
of
band
3,
the
major
transmembrane
protein
of
the
red
cell,
as
a
possible
site
for
interaction
with
P.
fakiparum
(Okoye
and
Bennett,
1985;
Friedman
et
al.,
1985).
The
physical
state
of
spectrin,
the
major
component
of
the
membrane
skeleton,
is
important
for
the
subsequent
interiorization
of
the
merozoite,
as
shown
by
strong
inhibi-
tion
of
the
process
following
limited
cross-
linking
of
spectrin
by
chemical
or
immunoche-
mical
means
(Dluzewski
et
al.,
1983a;
Olson
and
Kilejian,
1982).
Since
spectrin
is
linked
to
the
major
transmembrane
proteins,
it
may
play
a
role
in
the
redistribution
of
the
in-
tramembrane
particles
observed
during
the
invasion.
The
membrane
skeletal
proteins
could
also
play
a
role
in
modulating
mem-
brane
deformability
during
invasion.
-
It
is
of
interest
to
note
that
ovalocytic
erythrocytes
from
Melanesians
are
both
resistant
to
invasion
by
P.
falciparum
and
to
temperature-
induced
deformation
(Kidson
et
al.,
1981).
However,
hereditary
spherocytes,
also
with
reduced
deformability,
apparently
have
nor-
mal
susceptibility
to
invasion
(Koeweiden
et
al.,
1979).
Among
the
various
other
factors,
intraery-
throcytic,
ATP
was
shown
to
be
essential
in
promoting
invasion
(Olson
and
Kilejian,
1982;
Dluzewski
et
al.,
1983b).
The
function
of
ATP
is
probably
not
related
to
the
main-
tenance
of
cation
gradients,
but
probably
involves
phosphorylation
of
membrane
pro-
teins,
as
suggested
by
the
inability
of
non-
hydrolysable
ATP
to
replace
ATP.
Since
shedding
of
the
merozoite
surface
components
occur
during
invasion,
membrane-bound
protease
or
glycosidase
may
be
an
important
factor.
The
contents
of
merozoite
rhoptries
organelles
near
the
apical
end,
discharged
during
invasion
may
also
be
critical
for
the
process.
Some
rhoptry
proteins
have
been
shown
to
be
protective
antigens
in
P.
falci-
parum
(Holder
et
al.,
1985).
INTERACTION
DURING
INTRACEL-
LULAR
DEVELOPMENT
During
intracellular
development,
many
changes
occur
in
the
membrane
of
infected
Vol.
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December
1986
637
SOUTHEAST
ASIAN
J.
TROP.
MED.
PUB.
HLTH.
red
cells,
including
the
structure
and
function
of
the
protein
components,
the
composition
and
arrangement
of
phospholipid
components
and
the
appearance
of
new
parasite-derived
antigens
(Howard,
1982;
Newbold,
1984;
Sherman,
1984).
Red
cell
spectrin
has
been
shown
to
decrease
with
appearance
of
new
lower
molecular-weight
proteins
suggesting
that
spectrin
degradation
may
occur
during
development
of
various
species
of
malaria
parasites
(Weidekamm
et
al.,
1973;
Konigk
and
Mirtsch,
1977;
Yuthavong
et
al.,
1979).
A
cathepsin
D-like
protease
has
been
purified
from
P.
lophurae,
and
shown
to
produce
similar
degradative
changes
on
the
membrane
proteins
(Sherman
and
Tanigoshi,
1983).
Degradative
changes
of
membrane
skeleton
proteins
may
be
linked
with
shape
and
defor-
mability
changes
of
infected
cells,
and
may
be
relevant
to
the
mechanism
of
merozoite
release.
Red
cell
membrane
proteins
also
undergo
changes
other
than
degradation
during
ma-
larial
infection.
In
P.
berghei-infected
cells,
a
protein
of
molecular
weight
42,000
was
shown
to
undergo
phosphorylation
(Chaimanee
and
Yuthavong,
1979;
Wiser
et
al.,
1983).
Va-
rious
properties
of
this
protein
suggest
that
it
is
phosphorylated
actin,
and
the
level
of
phosphorylation
is
linked
with
osmotic
fragility
and
filterability
of
the
infected
cells
(Yuthavong,
1985).
Changes
in
antigenicity
of
the
host
red
cell
induced
by
the
parasite
has
important
implications
in
both
immunopathology
and
in
protective
immunity.
Some
antigens
appear
early
in
the
infection,
e.g.,
the
ring-
infected
erythrocyte
surface
antigen
(RESA)
in
P.
falciparum
infection
(Coppel
et
al.,
1984).
The
antigen
appears
to
be
identical
to
Pf155,
a
protein
of
molecular
weight
155,000,
the
antibody
to
which
could
effectively
pre-
vent
parasite
invasion
(Perlmann
et
al.,
1984).
Other
antigens
appear
in
the
later
stages
of
infection.
The
variant
antigen
on
P.
knowlesi-
infected
red
cells
responsible
for
schizont-
induced
cell
agglutination
(SICA
antigen)
is
one
such
example
(Newbold,
1984).
Another
example
is
the
antigen
of
molecular
weight
285,000
responsible
for
cytoadherence
of
knobby
red
cells
containing
K+
strains
of
P.
falciparum
(Leech
et
al.,
1984a).
K+
strains
of
P.
falciparum
has
a
histidine-rich
protein
(Kilejian,
1979)
which
binds
to
red
cell
membrane
skeleton
to
produce
cups
as
foci
for
knobs
on
the
cell
surface
(Leech
et
al.,
1984b).
It
is
perhaps
not
directly
involved
in
cytoadherence
but
in
presentation
of
the
cytoadherence
antigen.
Cytoadherence
is
important
for
the
sequestration
of
late-stage
P.
falciparum-infected
red
cells
along
the
endothelium
of
small
blood
vessels,
and
may
be
a
contributing
factor
to
cerebral
malaria.
Furthermore,
monocytes,
platelets
and
a
melanoma
cell
line
which
also
bind
infected
red
cells
appear
to
use
similar
receptors
for
the
binding
(Barnwell
et
a1.,
1985).
Thrombo-
spondin,
a
soluble
adhesive
glycoprotein
present
in
blood,
may
also
mediate
cyto-
adherence
(Roberts
et
al.,
1985).
Changes
in
the
function
of
malaria-infected
red
cell
membrane
include
enhancement
in
transport
of
cations,
anions
and
metabolites.
Increase
in
uptake
of
Ca
2
+
in
red
cells
infected
with
various
species
of
malaria
parasites
(Bookchin
et
al.,
1981;
Leida
et
al.,
1981;
Tanabe
et
al.,
1982;
Krungkrai
and
Yuthavong,
1983)
may
be
due
to
increased
membrane
permeability
compounded
by
reduced
pumping
activity.
Increase
in
per-
meability
of
anions
and
small
metabolites
may
be
due
to
increase
in
number
of
transport
channels
generated
by
parasite
protein
(Kut-
ner
et
al.,
1985).
The
transport
channels
exclude
disaccharides
or
larger
molecules,
and
are
positively
charged
(Ginsburg
et
al,.
1985).
The
selective
transport
increase
prob-
ably
serves
important
functions
in
supplying
the
parasite
with
required
nutrients
and
ions
for
its
metabolic
purposes.
638
Vol.
17
No.
4
December
1986
MALARIA
PARASITE
AND
RELL
CELL
MEMBRANE
SUMMARY
The
malaria
parasite
intimately
interacts
with
the
host
red
cell
membrane
throughout
the
cycle
of
invasion
and
intracellular
develop-
ment.
Direct
interaction
between
the
mero-
zoite
surface
and
the
red
cell
membrane
involves
specific
binding
between
the
surface
components
of
both
cells,
which
leads
to
the
subsequent
endocytotic
process
still
incom-
pletely
understood.
Intracellular
development
of
the
parasite
is
accompanied
by
various
changes
in
the
structure
and
function
of
red
cell
membrane
components.
Some
changes
may
benefit
parasite survival
while
others
trigger
host
immune
response.
An
under-
standing
of
both
the
direct
interaction
be-
tween
the
surface
components
of
the
parasite
and
the
red
cell
during
invasion,
and
the
subsequent
changes
in
the
red
cell
membrane
following
invasion,
should
lead
to
better
ways
of
controlling
malaria.
ACKNOWLEDGEMENTS
Research
in
the
author's
group
is
support-
ed
by
the
Programme
of
Great
Neglected
Diseases
of
Mankind
of
the
Rockefeller
Foundation,
and
WHO-TDR
Programme.
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