Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
42 Cards in this Set
- Front
- Back
|
Whats more successful: prevention or treatment?
|
Prevention, but can't prevent everything
|
|
|
How do you prevent malaria infections?
|
Insecticides like DDT
Bed nets |
|
|
What are the most effective treatments?
|
Drug resistance has reduced the effectiveness of several commonly used anti-malarials (ie CQ)
-->Artemisinin has shown promise in treating drug-resisting strains |
|
|
Will modifying mosquitoes so that they can't carry the disease work?
|
Not sure what will happen
The Plasmodium parasite might mutate to take over the genetically modified varieties |
|
|
What are some strategies to control malaria?
|
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) |
|
|
What are the drug transporters in malaria?
|
PfCRT
PfMDR1 |
|
|
What is PfCRT?
|
Plasmodium falciparum CQ resistance transporter
|
|
|
What does PfCRT do?
|
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 |
|
|
What is PfMDR1?
|
Plasmodium falciparum Multidrug Resistance Transporter
|
|
|
Describe PfMDR1
|
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 |
|
|
What's an important difference btw PfCRT and PfMDR1?
|
PfCRT ONLY transports CQ
|
|
|
What is needed for PfCRT to become resistance to CQ?
|
One mutation: K76T
-->Lysine 76 to threonine |
|
|
Which way does PfCRT pump CQ?
|
OUT of the digestive vacuole and into the cytosol
|
|
|
Where are the mutations in the PfMRD1?
|
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 |
|
|
What do all sensitive strains of the parasite have?
|
At least 1 copy of MDR (some have 2-3 copies)
|
|
|
What does the number of copies of MDR depend on?
|
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 |
|
|
What are the drug targets for the blood stages of the malaria parasite?
|
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 |
|
|
What is an important malaria drug target?
|
Apicoplast: only organelle thats completely different from humans
|
|
|
What are the Plasmodium species whose genomes have been completely sequenced?
|
P. falciparum
P. vivax P. knowlesi |
|
|
Describe the genome of P. falciparum
|
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 |
|
|
What are the origin of plastids?
|
Ancestral parasite ate a eukaryotic alga and retained the algal plastid
1st endosymbiosis: origin of chloroplast 2nd endosymbiosis: origin of the apicoplast |
|
|
Describe the plastid in plasmodium?
|
Organelle with 4 mbs
Confirmed by McFadden Vestigial plastid, of plant origin |
|
|
What was the actual plastid that was found in plasmodium?
|
Was actually apicoplast
4 mbs, extra-chromosomal DNA |
|
|
Describe the plasmodium apicoplast
|
Novel organelle
Acquired by 2ry endosymbiosis Harbors its own genome Essential for the survival of the parasite Apicoplast: apicomplexan + plastid |
|
|
Where was it the Plasmodium apicoplast derived from?
|
Probably green algae
Thoguht to be involved in the synthesis of lipids and several other compounds |
|
|
How many genes does the apicoplast encode?
|
~30 ptn coding genes
~30 RNA genes |
|
|
What are the new 3 drug targets?
|
3 pathways:
Isoprenoide pathway: Fosmidomycin, targets precursors for vitamins and ptn-anchor FA synthesis: Triclosan Shikimate synthesis: Glyphosphate, precursors for aromatic AA |
|
|
What is the shikimate pathway?
|
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 |
|
|
Describe the Shikimate path
|
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 |
|
|
What vacccine research is being done now for malaria?
|
Sporozoite stage
Asexual erythrocytic stage Sexual erythrocytic stage |
|
|
What is a vaccine vs sporozoite stage targeting?
|
Nlock hepatocyte invasion
Kill the sporozoite |
|
|
What is a vaccine vs the asexual erythrocytic stage against?
|
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 |
|
|
What is a vaccine targeting the sexual erythrocytic stage designed to do?
|
Kill gametocytes within iRBC
|
|
|
What is the current candidate vaccine?
|
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 |
|
|
Where did the RTS, S vaccine get its name?
|
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 |
|
|
Who is the vaccine for?
|
Children in endemic areas
Vaccine not as good as adult immunity, but still good |
|
|
What are the 5of the malaria target? stages
|
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 |
|
|
What is important about stage 1?
|
Understanding how the parasite develops in the mosquito and genetically modifying the mosquito to prevent transmission
|
|
|
What is important about stage 2?
|
Preventing parasite from leaving the liver and causing clinical disease
|
|
|
What is important about stage 3?
|
Investigating mb transport ptns during malaria infection
|
|
|
What is important about stage 4?
|
Using the mosquito immune system to kill the malaria parasite
|
|
|
What is important about stage 5?
|
Using the mosquito immune system to kill the malaria parasite
|
