* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Lecture_12_Jan 29_2015 Plasmodium_invasion
Survey
Document related concepts
Theories of general anaesthetic action wikipedia , lookup
Protein moonlighting wikipedia , lookup
SNARE (protein) wikipedia , lookup
Biochemistry wikipedia , lookup
G protein–coupled receptor wikipedia , lookup
Paracrine signalling wikipedia , lookup
Interactome wikipedia , lookup
Intrinsically disordered proteins wikipedia , lookup
Two-hybrid screening wikipedia , lookup
Cell-penetrating peptide wikipedia , lookup
Cell membrane wikipedia , lookup
Protein adsorption wikipedia , lookup
Proteolysis wikipedia , lookup
Protein–protein interaction wikipedia , lookup
Endomembrane system wikipedia , lookup
Transcript
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? # Jumbo Jets day