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Blood, 1 February 2002, Vol. 99, No. 3, pp. 1060-1063
RED CELLS
Contribution of parasite proteins to altered mechanical
properties of malaria-infected red blood cells
Fiona K. Glenister,
Ross L. Coppel,
Alan F. Cowman,
Narla Mohandas, and
Brian M. Cooke
From the Department of Microbiology, Monash University,
Clayton, Victoria, Australia; The Walter and Eliza Hall Institute of
Medical Research, Parkville, Victoria, Australia; and the Life Sciences
Division, Lawrence Berkeley Laboratory, CA.
 |
Abstract |
Red blood cells (RBCs) parasitized by Plasmodium
falciparum are rigid and poorly deformable and show abnormal
circulatory behavior. During parasite development, knob-associated
histidine-rich protein (KAHRP) and P falciparum erythrocyte
membrane protein 3 (PfEMP3) are exported from the parasite and interact
with the RBC membrane skeleton. Using micropipette aspiration, the
membrane shear elastic modulus of RBCs infected with transgenic
parasites (with kahrp or pfemp3 genes deleted)
was measured to determine the contribution of these proteins to the
increased rigidity of parasitized RBCs (PRBCs). In the absence of
either protein, the level of membrane rigidification was significantly
less than that caused by the normal parental parasite clone. KAHRP had
a significantly greater effect on rigidification than PfEMP3,
contributing approximately 51% of the overall increase that occurs in
PRBCs compared to 15% for PfEMP3. This study provides the first
quantitative information on the contribution of specific parasite
proteins to altered mechanical properties of PRBCs.
(Blood. 2002;99:1060-1063)
© 2002 by The American Society of Hematology.
| |
Introduction |
Malaria caused by Plasmodium falciparum
remains the most serious and widespread parasitic disease of humans.
Clinical symptoms of malaria occur during the asexual stage of the
parasite's life cycle, when it multiplies within red blood cells
(RBCs). The extreme virulence of P falciparum and the
occurrence of severe, often fatal clinical complications is related to
the ability of RBCs parasitized by mature forms of the parasite to
accumulate in the microvasculature of a variety of
organs.1 This abnormal circulatory behavior for RBCs
appears to be directly related to parasite-induced alteration of its
mechanical and adhesive properties.
During the last 2 decades, the altered adhesive properties of
parasitized RBCs (PRBCs) have been studied intensively (see 2,3 for recent reviews). In contrast, alterations of their mechanical properties, and the molecular mechanisms underpinning these
changes, have been relatively ignored. Previous studies have clearly
demonstrated that the deformability of intact PRBCs is profoundly
reduced.4-6 The overall increase in red cell rigidity is
due, in part, to the presence of the large, nondeformable intracellular parasite and to a number of stage-specific parasite-encoded proteins that associate with the RBC membrane skeleton.3,5,6
Paulitschke and Nash6 used micropipette aspiration to
measure the rigidity of RBCs parasitized by a number of unrelated
parasite lines of knobby and knobless phenotypes. In general, the
membranes of knobby PRBCs were more rigid than those lacking knobs;
however, there was considerable variation in rigidity, particularly
between knobby lines, with some knobby PRBCs only slightly more rigid
than others infected with knobless parasite lines. Unfortunately, in
their study, there was no characterization of the parasite genotype or
immunohistochemical analysis of the PRBCs to determine precisely which
parasite proteins were or were not expressed in different parasite
lines. As such, though increased membrane rigidity is likely to result
from the combined effect of a number of parasite proteins interacting
with the RBC membrane, the lack of a transfection system for P
falciparum to knock out individual genes has until now prevented
assessment of the contribution of individual proteins to membrane
rigidification. Although still in its infancy, a method to create
single gene knockouts in P falciparum is now available, and
2 well-characterized transgenic parasite clones are available for study
with specific deletions of the genes for 2 membrane skeleton-associated proteins, the knob-associated histidine rich protein (KAHRP)7 and P falciparum erythrocyte
membrane protein 3 (PfEMP3).8 In mature parasites, both
proteins are exported to the membrane skeleton of infected RBCs. KAHRP
binds to spectrin and actin,9 but the interaction of
PfEMP3 with the membrane skeleton is less well understood. Nonionic
detergent solubility experiments, however, strongly support a
noncovalent linkage of PfEMP3 to the RBC membrane
skeleton.10,11
In the current study, we have made use of these 2 transgenic
parasite lines in which the genes for KAHRP and PfEMP3 have been deliberately disrupted to determine, for the first time, the precise contribution of single, specific parasite proteins to the increased rigidity of the PRBC membrane. We demonstrate that both KAHRP and
PfEMP3 contribute to the increased rigidity of PRBCs and that the
contribution of KAHRP is significantly greater. Our study provides the
first quantitative information on the contribution of specific parasite
proteins to the altered mechanical properties of PRBCs and increases
our understanding of parasite proteins that strongly influence the
virulence of P falciparum.
| |
Materials and methods |
Parasitized red blood cells
Transgenic clones of P falciparum KKO
(kahrp gene knockout) and EMP3KO (pfemp3 gene
knockout) were generated from the well-characterized parasite clone 3D7
by transfection, as previously described.7,8 Parasites
were maintained in continuous in vitro culture in human RBCs using
standard procedures12 in HEPES-buffered RPMI 1640 containing AlbumaxII (Gibco BRL, Grand Island,
NY).13 For the transgenic clones, culture medium
was further supplemented with 0.1 µM pyrimethamine (Sigma Chemical,
St Louis, MO).7 Cultures of knob-expressing parasite
clones (3D7 and EMP3KO) were subjected to weekly flotation in gelatin
to maintain synchrony and expression of knobs, as recently
described.14 Synchronous cultures of the knobless clone
(KKO) were maintained by weekly selection for ring-stage parasites
using sorbitol, as previously described.15 Cultures were
used for experiments when most (more than 90%) of the parasites were
mature, pigmented trophozoites. Lack of expression of KAHRP or PfEMP3
in the transgenic clones was confirmed by immunofluorescence using
specific antisera and the presence or absence of membrane knobs
determined by transmission electron microscopy.7
Determination of membrane shear elastic modulus
The shear elastic modulus of the RBC membrane was determined by
micropipette aspiration, as previously described.5,6,16 Briefly, cultured PRBCs were diluted with culture medium further supplemented with 2% (wt/vol) bovine serum albumin to approximately 1 × 106 RBC/mL and introduced into a chamber
(approximately 2 mm deep) located on the stage of an inverted light
microscope (Leica DMIRB). Precision glass micropipettes (internal
diameter, 1.1-1.4 µm) with a long (approximately 8 mm) parallel taper
were fabricated, filled with phosphate-buffered saline, and connected
to a hydrostatic pressure system with a resolution of 0.01 mm
H2O. Pipettes were mounted on a hydraulic micromanipulator
(Narishige, Japan), maneuvered into the open side of the chamber and
visualized using a ×63, high numerical aperture (0.7) objective lens.
Images were viewed and analyzed on a high-resolution monitor using
customized digital image capture and analysis software (Total Turnkey
Solutions, Coburg, Victoria, Australia) (Figure
1). Under these conditions, malaria
parasites could easily be visualized within RBCs. To minimize potentially confounding factors such as abnormal cell morphology, reduced availability of free membrane, and large, rigid parasites in
PRBCs that could affect comparisons of the elastic modulus between
uninfected RBCs and PRBCs or between different parasite clones, only
PRBCs that remained approximately biconcave-discoid and contained a
single mature parasite that consumed no more than one third of the RBC
volume were selected for analysis. Membranes of individual RBCs were
aspirated progressively into the pipette using increasingly negative
suction pressures. The membrane shear elastic modulus was determined by
measuring the length of a membrane tongue (L) aspirated from the RBC
into the pipette for a range of aspiration pressures (P) and calculated
from the linear regression of dL/dP as previously
described.17 The range of aspiration pressures was 1.0 to
5.0 mm H2O for normal and uninfected RBCs or 1.0 to 10.0 mm
H2O for PRBCs. Membrane tongue lengths varied from 0.53 to
2.83 µm for normal/ uninfected RBCs and from 0.40 to 2.65 µm for
PRBCs. Calculation and comparison of shear elastic moduli was valid
given that over these ranges, normal/uninfected RBCs and PRBCs behaved
as if elastic with linear extension. Linear regression of dL/dP for all
cells tested gave comparable mean Pearson correlation coefficients of
0.95 for normal/uninfected RBCs and 0.96 for PRBCs. All measurements
were performed at room temperature (20°C-25°C).
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| Figure 1.
Determination of membrane shear elastic modulus by
micropipette aspiration.
Bright-field digitally captured images of a typical micropipette (1.3 µm internal diameter) used for determination of the shear elastic
modulus of (A) an uninfected RBC and (B) an RBC infected with a mature
malaria (P falciparum) parasite as described in "Materials
and methods." A portion of the RBC membrane aspirated into the
pipette can be visualized clearly, shown here at a pressure of 2.0 mm
H2O (A) and 4.0 mm H2O (B). Note that in panel
B, only PRBCs that remained approximately discoid and that contained
relatively small but mature trophozoites were measured so that there
was sufficient free membrane to aspirate away from the parasite itself.
Scale bar, 5 µm.
|
|
| |
Results |
For all parasite clones, the presence of mature pigmented
trophozoites within RBCs was associated with marked rigidification of
the RBC membrane and with the parental clone, 3D7 showing, on average,
a 137% increase in elastic modulus when compared with uninfected RBCs
(Figure 2). Interstrain variability,
particularly between knobby parasite lines, has been observed
previously, with increases in membrane rigidity ranging from 90% to
300% for knobby strains when compared with nonparasitized
RBCs.6 The increase in elastic modulus caused by parasite
clone 3D7 tested in this study appears to lie at the lower end of this
range. Although all cultures were stage synchronized to minimize
effects on the elastic modulus caused by differences in parasite age,
there is still considerable variation in the moduli between different
PRBCs. The magnitude of the variance of the data, however, is similar for the different parasite lines tested and for uninfected RBCs, suggesting that this variation is unlikely to be a major confounding factor influencing comparisons of elastic modulus between the different
parasite clones.
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| Figure 2.
Effect of KAHRP and PfEMP3 on the membrane shear elastic
modulus of red blood cells infected by mature stages of
P falciparum. Membrane shear elastic modulus of
normal, uninfected, and parasitized RBCs was measured by micropipette
aspiration in 5 (for normal RBCs) to 8 (for uninfected RBCs and PRBCs)
separate experiments as described in "Materials and methods."
Different pipettes were used throughout the study, but in each
experiment the same pipette was used to measure uninfected RBCs and
PRBCs. Normal RBCs were from freshly drawn human venous blood and were
suspended in fresh parasite culture medium supplemented with 2% bovine
serum albumin. Uninfected RBCs were nonparasitized RBCs from each of
the 3 different parasite cultures. Each point represents the shear
elastic modulus for an individual RBC. Solid horizontal bars represent
the mean of all data in each group. Significant differences between
pairs of parasite clones are shown as **(P < .01) and
***(P < .001) by the Mann-Whitney U
test.
|
|
Membranes of RBCs parasitized by knobby clones (3D7 or EMP3KO) were
significantly more rigid than those infected with the knobless
kahrp knockout clone (P < .001) (Figure 2). In
the absence of KAHRP (and membrane knobs), the increase in membrane
rigidity of PRBCs over uninfected RBCs was approximately halved
compared with the increase that occurred in RBCs parasitized by the
knobby parental parasite clone. Similarly, loss of PfEMP3 (without loss of KAHRP or knobs) also reduced the maximum level of membrane rigidification, though its contribution was far less pronounced than
that caused by KAHRP (Figure 2).
| |
Discussion |
A number of reasons might account for the difference in the level
of rigidification caused by these 2 proteins. One is that there is
indirect evidence, based on the relative abundance of mRNA, that KAHRP
may be more abundant in PRBCs than PfEMP3.18 Such
estimates, however, are complicated by the repetitive nature of the
coding sequences of these 2 genes, preventing simple conclusions being
drawn based on antibody reactivity. Another is that, unlike KAHRP,
PfEMP3 does not cluster in high density at knobs but assumes a more
even distribution around the membrane skeleton,11 possibly influencing the magnitude of its effect. At present, we cannot rule out
the possibility that the effect of loss of either of these proteins on
membrane rigidity may occur as an indirect consequence of loss or
altered level of expression of some other, perhaps currently
unidentified, protein at the membrane skeleton.
In normal RBCs, tetramers of spectrin, actin, proteins 4.1 and 4.2, ankyrin, and adducin interact to form a complex, ordered network that
underlies the RBC lipid membrane. The membrane and cytoskeleton are
connected to each other through interactions between ankyrin and the
RBC anion transporter band 3 and protein 4.1 with integral membrane
sialoglycoproteins, predominantly glycophorin A.19,20
Maintenance of the physiological deformability of normal RBCs is highly
dependent on the preservation of this well-defined architecture of the
membrane skeleton and a highly elastic membrane.21 Abnormal molecular interactions that result in cross-linking of cytoskeletal proteins can markedly increase the rigidity of RBCs, as
evidenced by the reduced deformability of RBCs treated with monoclonal
antibodies to glycophorin A that spans the RBC membrane and interacts
with spectrin through protein 4.1.22 Although the precise
mechanisms leading to decreased deformability of PRBCs are poorly
understood, the contribution of parasite proteins to increased membrane
rigidity is most likely attributed to their direct or indirect
interactions with proteins of the RBC membrane skeleton. KAHRP is known
to associate with spectrin, actin, and ankyrin in the RBC
skeleton9,23,24 and may cross-link spectrin, resulting in increased membrane rigidity. Treatment of RBCs with oxidative agents, known to cause protein-protein cross-linking, markedly decreases RBC deformability because of the formation of
oxidative cross-links between individual spectrin tetramers and between
spectrin and hemoglobin.23,25-27 Such cross-linking of
spectrin tetramers within the skeletal network could limit the extent
of extension and folding of spectrin during cell deformation and
subsequently increase membrane rigidity.
The net effect of the various malaria proteins at the membrane skeleton
of PRBCs appears to effectively increase the level of cross-linking of
spectrin by the formation of many protein-protein interactions,
resulting in a more robust RBC that is more resistant to destruction
during parasite development. In addition to binding to the RBC
cytoskeleton by a direct interaction with spectrin, and possibly
actin,28-30 KAHRP also anchors the parasites' exported cytoadherence ligand, PfEMP1, to the RBC membrane through an
interaction of KAHRP with the cytoplasmic tail of
PfEMP1.28 In this way, interactions of KAHRP
with spectrin and PfEMP1, which spans the RBC membrane, would cause
additional increases in the rigidity of the membrane skeleton. Further
study of parasite lines that do not express PfEMP1 would be useful to
address the contribution of KAHRP-PfEMP1 associations to increased
PRBC rigidity.
Finally, there is evidence to suggest that mature parasites release
exo-antigens that may increase the rigidity of uninfected RBCs.5,31,32 Here, we have quantified and compared the
elastic moduli for normal, noncultured RBCs and uninfected RBCs
cultured in the presence of malaria parasites. In contrast to previous studies, we found no significant increases in the rigidity of uninfected RBCs (Figure 2).
In conclusion, our study provides the first critical assessment of the
contribution and importance of individual parasite proteins to the
altered mechanical properties of PRBCs. The results add significantly
to our understanding of proteins that contribute to the extreme
virulence of falciparum malaria and, in the broader sense, increase our
knowledge of cytoskeletal interactions that maintain and regulate
cellular mechanical properties.
| |
Acknowledgments |
We thank Professor Gerard Nash (The University of Birmingham,
United Kingdom) for expert advice and assistance.
| |
Footnotes |
Submitted July 5, 2001; accepted September 24, 2001.
Supported by the National Health and Medical Research Council of
Australia (NHMRC), The Wellcome Trust, and the National Institutes of
Health (NIH) (DK32094-10).
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Brian M. Cooke, Dept of Microbiology, PO Box 53, Monash University, Clayton, Victoria 3800, Australia; e-mail:
brian.cooke{at}med.monash.edu.au.
| |
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Abstract
Introduction