EU BIOC 310 2016
MOLECULAR INTERACTION OF PLASMODIUM WITH MAMALIAN HOST CELL
Merozoites rapidly (approximately 20 seconds)
and specifically enter erythrocytes. This
specificity is manifested both for erythrocytes as
the preferred host cell type and for a particular
host species, thus implying receptor-ligand
interactions.
Substantial progress has been made in
identifying many of the parasite and host
proteins that are important for the invasion
process.
Four distinct steps in the invasion process can be recognized (Figure):
1. initial merozoite binding
2. reorientation and erythrocyte deformation
3. junction formation
4. parasite entry
Merozoite Surface Proteins and Host-Parasite Interactions
The initial interaction between the merozoite and the erythrocyte is probably a random collision
and presumably involves reversible interactions between proteins on the merozoite surface and
the host erythrocyte. The best characterized is merozoite surface protein-1 (MSP-1).
Circumstantial evidence implicating MSP-1 in erythrocyte invasion includes its uniform
distribution over the merozoite surface and the observation that antibodies against MSP-1 inhibit
invasion. In addition, MSP-1does bind to band 3. The band 3 protein is a 95 kDa multipass
membrane protein that exchanges bicarbonate ion for chloride ion. It is the predominant
membrane transporter in red blood cells and plays a central role in structure and function of those
cells and in acid-secreting cells in the kidney. Band 3 also appears to contribute significantly to
maintaining cell shape, in particular, the biconcave shape of erythrocytes.
Another interesting aspect of MSP-1 is the proteolytic processing that is coincident with
merozoite maturation and invasion. A primary processing occurs at the time of merozite
maturation and results in the formation of several polypeptides held together in a non-covalent
complex.
A secondary processing occurs coincident with merozoite invasion at a site near the C-terminus.
The non-covalent complex of MSP-1 polypeptide fragments is shed from the merozoite surface
following proteolysis and only a small C-terminal fragment is carried into the erythrocyte. This
loss of the MSP-1 complex may correlate with the loss of the 'fuzzy' coat during merozoite
invasion. The C-terminal fragment is attached to the merozoite surface by a GPI anchor and
consists of two EGF-like modules (epidermal growth factor (EGF)-like module. A small
structural domain, or motif, within a protein. The EGF-like domain is characterized by spacing
of cysteine residues which form disulfide bonds). EGF-like modules are found in a variety of
proteins and are usually implicated in protein-protein interactions. One possibility is that the
1
, EU BIOC 310 2016
secondary proteolytic processing functions to expose the EGF-like modules which strengthen the
interactions between merozoite and erythrocyte. The importance of MSP-1 and its processing are
implied from the following observations:
vaccination with the EGF-like modules can protect against malaria, and
inhibition of the the proteolytic processing blocks merozoite invasion.
Other merozoite surface proteins are also involved in the interation of the merozoite with the
erythrocyte.
Reorientation and Secretory Organelles
After binding to the erythrocyte, the parasite reorients Apical Organelles of
itself so that the 'apical end' of the parasite is Plasmodium Merozoites
juxtaposed to the erythrocyte membrane. This
merozoite reorientation also coincides with a transient Organelle Shape Size (nm)
erythrocyte deformation. Apical membrane antigen-1
(AMA-1) has been implicated in this reorientation.
AMA-1 is a transmembrane protein localized at the
apical end of the merozoite and binds erythrocytes. Microneme ellipsoidal 40 x 100
Antibodies against AMA-1 do not interfer with the Rhoptry teardrop 300 x 600
initial contact between merozoite and erythrocyte thus
Dense Granule spherical 120-140
suggesting that AMA-1 is not involved in merozoite
attachement. But antibodies against AMA-1 prevent the reorientation of the merozoite and
thereby block merozoite invasion.
Specialized secretory organelles are located at the apical end of the invasive stages of
apicomplexan parasites. Three morphologically distinct apical organelles are detected by
electron microscopy: micronemes, rhoptries, and dense granules (Table). Dense granules are not
always included with the apical organelles and probably represent a heterogeneous population of
secretory vesicles.
The contents of the apical organelles are
expelled as the parasite invades, thus
suggesting that these organelles play
some role in invasion. Experiments in
Toxoplasma gondii indicate that the
micronemes are expelled first and occur
with initial contact between the parasite
and host. An increase in the cytoplasmic
concentration of calcium is associated
with microneme discharge, as is typical
of regulated secretion in other
eukaryotes.
The rhoptries are discharged immediately after the micronemes and the release of their contents
correlate with the formation of the parasitophorous vacuole.
2
MOLECULAR INTERACTION OF PLASMODIUM WITH MAMALIAN HOST CELL
Merozoites rapidly (approximately 20 seconds)
and specifically enter erythrocytes. This
specificity is manifested both for erythrocytes as
the preferred host cell type and for a particular
host species, thus implying receptor-ligand
interactions.
Substantial progress has been made in
identifying many of the parasite and host
proteins that are important for the invasion
process.
Four distinct steps in the invasion process can be recognized (Figure):
1. initial merozoite binding
2. reorientation and erythrocyte deformation
3. junction formation
4. parasite entry
Merozoite Surface Proteins and Host-Parasite Interactions
The initial interaction between the merozoite and the erythrocyte is probably a random collision
and presumably involves reversible interactions between proteins on the merozoite surface and
the host erythrocyte. The best characterized is merozoite surface protein-1 (MSP-1).
Circumstantial evidence implicating MSP-1 in erythrocyte invasion includes its uniform
distribution over the merozoite surface and the observation that antibodies against MSP-1 inhibit
invasion. In addition, MSP-1does bind to band 3. The band 3 protein is a 95 kDa multipass
membrane protein that exchanges bicarbonate ion for chloride ion. It is the predominant
membrane transporter in red blood cells and plays a central role in structure and function of those
cells and in acid-secreting cells in the kidney. Band 3 also appears to contribute significantly to
maintaining cell shape, in particular, the biconcave shape of erythrocytes.
Another interesting aspect of MSP-1 is the proteolytic processing that is coincident with
merozoite maturation and invasion. A primary processing occurs at the time of merozite
maturation and results in the formation of several polypeptides held together in a non-covalent
complex.
A secondary processing occurs coincident with merozoite invasion at a site near the C-terminus.
The non-covalent complex of MSP-1 polypeptide fragments is shed from the merozoite surface
following proteolysis and only a small C-terminal fragment is carried into the erythrocyte. This
loss of the MSP-1 complex may correlate with the loss of the 'fuzzy' coat during merozoite
invasion. The C-terminal fragment is attached to the merozoite surface by a GPI anchor and
consists of two EGF-like modules (epidermal growth factor (EGF)-like module. A small
structural domain, or motif, within a protein. The EGF-like domain is characterized by spacing
of cysteine residues which form disulfide bonds). EGF-like modules are found in a variety of
proteins and are usually implicated in protein-protein interactions. One possibility is that the
1
, EU BIOC 310 2016
secondary proteolytic processing functions to expose the EGF-like modules which strengthen the
interactions between merozoite and erythrocyte. The importance of MSP-1 and its processing are
implied from the following observations:
vaccination with the EGF-like modules can protect against malaria, and
inhibition of the the proteolytic processing blocks merozoite invasion.
Other merozoite surface proteins are also involved in the interation of the merozoite with the
erythrocyte.
Reorientation and Secretory Organelles
After binding to the erythrocyte, the parasite reorients Apical Organelles of
itself so that the 'apical end' of the parasite is Plasmodium Merozoites
juxtaposed to the erythrocyte membrane. This
merozoite reorientation also coincides with a transient Organelle Shape Size (nm)
erythrocyte deformation. Apical membrane antigen-1
(AMA-1) has been implicated in this reorientation.
AMA-1 is a transmembrane protein localized at the
apical end of the merozoite and binds erythrocytes. Microneme ellipsoidal 40 x 100
Antibodies against AMA-1 do not interfer with the Rhoptry teardrop 300 x 600
initial contact between merozoite and erythrocyte thus
Dense Granule spherical 120-140
suggesting that AMA-1 is not involved in merozoite
attachement. But antibodies against AMA-1 prevent the reorientation of the merozoite and
thereby block merozoite invasion.
Specialized secretory organelles are located at the apical end of the invasive stages of
apicomplexan parasites. Three morphologically distinct apical organelles are detected by
electron microscopy: micronemes, rhoptries, and dense granules (Table). Dense granules are not
always included with the apical organelles and probably represent a heterogeneous population of
secretory vesicles.
The contents of the apical organelles are
expelled as the parasite invades, thus
suggesting that these organelles play
some role in invasion. Experiments in
Toxoplasma gondii indicate that the
micronemes are expelled first and occur
with initial contact between the parasite
and host. An increase in the cytoplasmic
concentration of calcium is associated
with microneme discharge, as is typical
of regulated secretion in other
eukaryotes.
The rhoptries are discharged immediately after the micronemes and the release of their contents
correlate with the formation of the parasitophorous vacuole.
2
