What is a hypnozoite?
A dormant form of the parasite that stays in the liver, found in relapsing malaria.
Describe the key stages of Plasmodium in the mosquito.
- Male and female gametocytes ingested during blood meal.
- Microgametes penetrates macrogametes to form diploid zygotes.
- Zygote becomes motile and elongated (ookinete), invades midgut wall and develops into oocyst.
- Oocyst ruptures, sporozoites move to salivary glands.
Describe key stages of Plasmodium in human liver cells.
- Sporozoites invade the liver (2 mins of bite).
- They mature into schizonts.
- Schizonts rupture to release merozoites.
Describe key stages of Plasmodium in human red blood cells.
- Merozoites invade RBC.
- Parasite digests haemoglobin (needs space to grow) and forms haemozoin.
- Schizonts rupture releasing merozoites. Cycle continues.
- Some parasites develop into gametocytes and are taken back up by the mosquito.
Why are only ring parasites of falciparum found in the blood?
Cytoadherence. Cell to cell adhesion to endothelial cells results in sequestration of parasites in capillaries. Escapes removal by spleen and can mature into a schizont.
What is haemozoin?
A by-product of parasites metabolic processes when it breaks down haemoglobin in the RBC. It is released when RBC ruptures and is taken up by the WBC.
name the malaria vaccine in trials and what stage does it target?
RTS-S, targets the pre-erythrocytic stage in the liver
What are the targets for chemotherapy for malaria?
Erythrocytic cycle in blood to relieve clinical symptoms.
Liver stage for prophylaxis.
Gametocytes to reduce transmission.
What is the extrinsic incubation period?
The time taken for the parasite to develop in the mosquito. This is shorter when it is warmer.
What is meant by the term vectorial capacity?
The total number of potentially infectious bites that would eventually arise from all the mosquitoes biting a single perfectly infectious human on a single day. (i.e. all mosquito bites=infection)
How do you calculate vectorial capacity?
ma^2p^n / -ln(p) m= vector:host ratio a= human biting rate p=mosquito survival through one day n= extrinsic incubation of parasite in days
What new solutions are there to resistance of insecticides?
- new insecticides for IRS (bendiocarb)
- Add synergists to bed nets (PBO) which blocks resistance causing enzymes in mosquitoes.
- larval source management (insecticides, predatory fish, biodegradable films that suffocate larvae, toxic bacteria, drainage)
- zooprophylaxis
- attractive targeted sugar baits (but will kill all pollinators)
- Screening houses
What are the malaria chemotherapy targets?
- Liver stages- prophylaxis
- Intraerythrocytic cycle - relieve clinical symptoms
- Gametocytes- prevent transmission
Define drug resistance
The ability of an organism to multiply and survive in the presence of concentrations of drug that normally destroy it or prevent its multiplication.
Define treatment failure
Inability to clear malarial parasitemia or resolve clinical symptoms despite administration os an antimalarial medicine.
What factors does resistance to antimalarials depend on?
Mutation rate
Pharmacodynamics
Pharmacokinetics
What is pharmacodynamics?
The effects of drugs and the mechanism of their action
If IC50 range for a drug is high, what does this mean in terms of resistance?
Parasites have greater chance of becoming resistant to the drug when the sub-lethal drug concentration range is high.
How can you reduce the spread of resistant parasites when designing a new drug
Target gametocytes, reduces transmission of resistant parasites
Define pharmacokinetics
What the body does to a drug
- absorption
- bioavailability
- distribution
- metabolism
- excretion
What is the ideal therapeutic half life of an antimalarial?
-Fast clearance time that reduces the exposure of the parasite to sub-lethal drug concentrations
BUT
- not too fast so that the drug has not had time to act
e.e. Artemisinins = 45mins
What are the 5 categories of drug resistance mechanisms?
- altered drug transport
- alternative target
- drug metabolism
- cellular repair mechanisms
- substrate competition
What mechanisms of altered drug transport resistance are there?
Increased efflux
Decreased uptake
Re-distribution to a non-target site
What does chloroquine target? What are the resistance mechanisms against it?
Binds haeme to stop parasite digesting haemoglobin.
Point mutation in transporter gene (PfCRT) which is found in membrane of digestive vacuole of parasite, preventing accumulation of the drug in the digestive vacuole of the pathogen.
