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42 Cards in this Set
- Front
- Back
Whats more successful: prevention or treatment?
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Prevention, but can't prevent everything
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How do you prevent malaria infections?
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Insecticides like DDT
Bed nets |
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What are the most effective treatments?
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Drug resistance has reduced the effectiveness of several commonly used anti-malarials (ie CQ)
-->Artemisinin has shown promise in treating drug-resisting strains |
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Will modifying mosquitoes so that they can't carry the disease work?
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Not sure what will happen
The Plasmodium parasite might mutate to take over the genetically modified varieties |
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What are some strategies to control malaria?
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Organized health care delivery
Sustainable vector control (bed nets, house spraying) New anti-malarial drugs in combination (cheap and easy to use) Understanding drug resistance Understanding the basic biology of the parasite to find new targets for drug development Vaccine development (as a supplement) |
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What are the drug transporters in malaria?
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PfCRT
PfMDR1 |
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What is PfCRT?
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Plasmodium falciparum CQ resistance transporter
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What does PfCRT do?
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Drug metabolite transporter superfamily
Transmb ptn found on the digestive (food) vacuole 10 transmb spanning domains Specific mutaions within this transporter responsible for CQ resistance Efflux transporter/pump, releasing CQ out of the digestive vacuole and into the cytosol |
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What is PfMDR1?
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Plasmodium falciparum Multidrug Resistance Transporter
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Describe PfMDR1
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ATP binding cassette (ABC) superfamily
Transmb ptn found on digewstive vacuole of the blood stage malaria parasite 1 transmb spanning domains Specific mutations within this transporter thought to be responsible for various drug resistance Transport of solutes/drugs INTO the digestive vacuole and away from the cytosol of the parasite |
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What's an important difference btw PfCRT and PfMDR1?
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PfCRT ONLY transports CQ
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What is needed for PfCRT to become resistance to CQ?
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One mutation: K76T
-->Lysine 76 to threonine |
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Which way does PfCRT pump CQ?
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OUT of the digestive vacuole and into the cytosol
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Where are the mutations in the PfMRD1?
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There are 5 mutations
-->Mostly in the mb spanning domain, 1 in the nucleotide binding domain None of them are specific for a particular drug |
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What do all sensitive strains of the parasite have?
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At least 1 copy of MDR (some have 2-3 copies)
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What does the number of copies of MDR depend on?
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Depends on drug pressure
(i.e. more mefloquine, more pressure) # of copies depends on the region and what drug was used/ concentration of the drugs |
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What are the drug targets for the blood stages of the malaria parasite?
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Cytosol: metabolic paths, i.e. folate metabolism ==>pyrimethamine/sulfadoxine; glycolysis ==> parasite has unique binding site for NADH cofactor
Parasite mb: phospholipid synthesis ==> doxycyclin Digestive vacuole: Hb degradation ==> quinine, CQ Mitochondrion: primaquine, atovaquone |
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What is an important malaria drug target?
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Apicoplast: only organelle thats completely different from humans
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What are the Plasmodium species whose genomes have been completely sequenced?
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P. falciparum
P. vivax P. knowlesi |
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Describe the genome of P. falciparum
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14 linear CHR
22.8 megabases 5400 genes 35kb circular plastid genome 6 kb mitochondrial genome 80% overall AT content (.: harder to express genes in bact/yeast) High coding density 60% of genes have an unknown fct |
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What are the origin of plastids?
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Ancestral parasite ate a eukaryotic alga and retained the algal plastid
1st endosymbiosis: origin of chloroplast 2nd endosymbiosis: origin of the apicoplast |
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Describe the plastid in plasmodium?
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Organelle with 4 mbs
Confirmed by McFadden Vestigial plastid, of plant origin |
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What was the actual plastid that was found in plasmodium?
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Was actually apicoplast
4 mbs, extra-chromosomal DNA |
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Describe the plasmodium apicoplast
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Novel organelle
Acquired by 2ry endosymbiosis Harbors its own genome Essential for the survival of the parasite Apicoplast: apicomplexan + plastid |
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Where was it the Plasmodium apicoplast derived from?
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Probably green algae
Thoguht to be involved in the synthesis of lipids and several other compounds |
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How many genes does the apicoplast encode?
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~30 ptn coding genes
~30 RNA genes |
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What are the new 3 drug targets?
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3 pathways:
Isoprenoide pathway: Fosmidomycin, targets precursors for vitamins and ptn-anchor FA synthesis: Triclosan Shikimate synthesis: Glyphosphate, precursors for aromatic AA |
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What is the shikimate pathway?
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Conserved in plants, algae, bacteria, fungi and several apicomplexan parasites
Series of 7 enz that generate the aromatic precursor chorismate from simple products of carbohydrate metabolism Shikimate path is required in Apicomplexa for the supply of folate precursors, required for parasite growth |
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Describe the Shikimate path
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7 enz that link the metabolism of carbs to biosynthesis of aromatic cpmds
Chorismate is metabolized to para-amino-benzoate (pABA), ubiquinne, and the aromatic AA |
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What vacccine research is being done now for malaria?
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Sporozoite stage
Asexual erythrocytic stage Sexual erythrocytic stage |
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What is a vaccine vs sporozoite stage targeting?
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Nlock hepatocyte invasion
Kill the sporozoite |
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What is a vaccine vs the asexual erythrocytic stage against?
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Agglutinate the merozoites before schizont rupture
Block merozoite invasion of RBCs Prevent cytoadherence of iRBCs by blocking receptor ligand interaction (CD-36) Neutralize harmful soluble paraasite toxins |
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What is a vaccine targeting the sexual erythrocytic stage designed to do?
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Kill gametocytes within iRBC
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What is the current candidate vaccine?
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Consists of sequences of the circumsporozoites (CS) ptn of the parasite and the hep B surface Ag (HBsAg)
Started pivotal stage III Designed for children resident in malaria-endemic areas |
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Where did the RTS, S vaccine get its name?
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R: gene for a ptn contianing the Ab-inducing repeat
T: portion recognized by T-cell WBCs S: Hep B surface Ag The surface Ag ptn lost its knack for self-assembly Fine tuning showed the combination one part RTS, to 4 parts S |
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Who is the vaccine for?
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Children in endemic areas
Vaccine not as good as adult immunity, but still good |
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What are the 5of the malaria target? stages
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1: Mosquito trabsnits parasite to humans
2: Liver stage parasite develops in liver and releases into blood 3: Blood stage parasite develops in blood, causing malaria 4: Mosquito ingests parasite from human 5: Mosquito stage parasite develops in mosquito gut and spreads to salivary glands |
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What is important about stage 1?
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Understanding how the parasite develops in the mosquito and genetically modifying the mosquito to prevent transmission
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What is important about stage 2?
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Preventing parasite from leaving the liver and causing clinical disease
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What is important about stage 3?
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Investigating mb transport ptns during malaria infection
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What is important about stage 4?
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Using the mosquito immune system to kill the malaria parasite
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What is important about stage 5?
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Using the mosquito immune system to kill the malaria parasite
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