Transcript Lecture_12_Jan 29_2015 Plasmodium_invasion

Plasmodium Invasive
Stages
ookinete (motile)
• mosquito gut
epithelial cells
sporozoite (motile)
• mosquito salivary
glands
• hepatocytes
merozoite (non-motile)
• erythrocytes
• Merozoite invasion
involves specific
interactions with the
host erythrocyte.
• The actively growing
parasite places metabolic
and other demands on
the host cell.
• Ultrastructural modifications are evident in the
infected erythrocyte.
Steps in Merozoite Invasion
Merozoite reorientation is accompanied by erythrocyte deformation.
Secretory (Apical) Organelles
Organelle
Shape
Rhoptry
Microneme
Dense Granule
Teardrop
Ellipsoidal
Spherical
Size (nm)
300 x 600
40 x 100
120 - 140
Proteins Localized to Micronemes
•Merozoite proteins:
• EBA-175 (sialic binding protein of P. falciparum)
• Duffy-binding protein (P. vivax and P. knowlesi)
•TRAP family*:
• SSP2 (sporozoite surface protein-2)  TRAP
(thrombospondin-related adhesive protein)
• Toxoplasma, Eimeria and Cryptosporidium
proteins with homology to SSP2/TRAP
• CTRP, circumsporozoite- and TRAP-related
protein (Plasmodium ookinete stage)
*Thrombospondin family functions in cell-cell and cell-matrix
interactions.
Invasion Receptors/Ligands
Species
P. falciparum
P. vivax,
P. knowlesi
Host
Receptor
Merozoite
Ligand
glycophorins
(sialic acid)
EBA-175
Duffy Ag
DBP
• microneme secretion
• receptor-ligand
interactions
• junction formation
Electron micrograph from Aikawa et al
(1978) J. Cell Biol. 77:72
Events correlated with entry
• clearance of erythrocyte
membrane proteins
• host membrane
invagination
• vacuolar membrane
formation
• junction becomes
an annulus
Are rhoptries involved in PVM formation?
Merozoite invasion:
a complex and ordered process
• Initial Binding
• merozoite surface proteins (eg, MSP-1)?
• Reorientation?
• Microneme Discharge and Junction Formation
• receptor-ligand interactions
• Ca2+ signal?
• Rhoptry Discharge and Vacuole Formation
• clearing of host membrane proteins
• Parasite Entry
• mediated by actin-myosin
• MSP-1 proteolysis and shedding of surface coat?
• Closure of PVM and Erythrocyte Membrane
• Merozoite invasion
involves specific
interactions with the
host erythrocyte.
• The actively growing
parasite places metabolic
and other demands on
the host cell.
• Ultrastructural modifications are evident in the
infected erythrocyte.
UPTAKE AND PERMEABILITY
The malaria parasite has a high metabolic rate and has a large demand
for small molecular metabolites that will serve as precursors for the
synthesis of nucleic acids, proteins and lipids.
The erythrocyte has a rather sluggish metabolism and limited transport
capabilities, but infected erythrocytes exhibit a substantial increase in
permeability to low molecular weight solutes.
Metabolites need to cross the PVM and the parasite plasma membrane. A
channel on the PVM has been implicated in the acquistion of nutrients.
Others have proposed a direct connection to the host plasma via a
'parasitophorous duct‘. Presumably the parasite plasma membrane has
transporters which are typical of other eukaryotes.
REDOX METABOLISM
A bi-product of metabolism and respiration are reactive oxygen
intermediates (ROI) such as superoxide, hydroxyl radical and hydrogen
peroxide. In particular, the digestion of oxy-hemoglobin results in the
production of ROI. These ROI can damage lipids, proteins and nucleic
acids and therefore need to be oxidized to oxygen and water.
Parasite enyzmes involved in redox metaboism have been identified.
Superoxide dismutase (SOD), catalase, and glutathione peroxidase are
involved in the detoxification of ROI. Oxidized glutathione is recycled by
glutathione reductase and the reducing equivalents of NADPH are
probably generated through the pentose phosphate cycle.
• Merozoite invasion
involves specific
interactions with the
host erythrocyte.
• The actively growing
parasite places metabolic
and other demands on
the host cell.
• Ultrastructural modifications are evident in the
infected erythrocyte.
Several Parasite Proteins Are Associated with Knobs
• KAHRP and PfEMP2 are believed to interact with the
submembrane cytoskeleton of the host erythrocyte
• reorganization of the membrane skeleton may result in
knob formation
• PfEMP1 crosses the erythrocyte membrane and is
exposed on the surface
• the acidic domain (C-terminus) interacts with the
basic KAHRP and cytoskeletal proteins
Invasion Receptors/Ligands
Species
P. falciparum
P. vivax,
P. knowlesi
Host
Receptor
Merozoite
Ligand
glycophorins
(sialic acid)
EBA-175
Duffy Ag
DBP
Human malaria: adaptations to the parasite
1) Sickle Cell- single point mutation- abnormal shape of a percentage of RBC
will not allow parasite development
RBC have bumps on surface- stick to capillary walls, loss of
potassium, parasites inside die, damaged cells removed
Only benefit is to heterozygous individuals:
double dominant are susceptible
double recessive often die from anemia
Example of strong evolutionary pressure to respond to a parasite
2) G-6-Phosphate dehydrogenase deficiency: results in reduced parasitemias
3) Duffy Blood group: double recessive- completely resistant to P. vivax.
parasite cannot find receptors to enter RBC
Found in 80% of W. African black population
Future of malaria management
New drugs
New insecticides
Greater involvement by governments in vector control and monitoring
Habitat manipulation to reduce mosquito populations
Involve people in their own primary health care
Transgenic mosquitoes- resistant to Plasmodium sp.
Malaria Cases
Number of deaths / year
Deaths/day
3,000,000
8,200
20
2,000,000
5,500
14
HOW MANY HAVE DIED IN THIS 1 HOUR LECTURE?
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