VJ - Antimalarials I Flashcards
What is Malaria? (3)
- Derived from Old Italian “mal aria” (bad air)
- Caused by Plasmodium spp. via Anopheles mosquitoes
- One of the “big three” killers (with HIV & TB)
What are the primary regions where malaria is endemic? (3)
- Most of Africa
- Half of South America
- Parts of Southeast Asia
Why have malaria case reductions slowed since 2000? (3)
- Funding and resource limitations
- Resistance (mosquito and Plasmodium)
- Impact of COVID-19
What is the name of the mosquito vector and how is it distributed?
Vector: Plasmodium transmitted by female Anopheles mosquitoes (~40 species linked to malaria).
Distribution: Widespread globally, especially in tropical/sub-tropical areas; common near stagnant water (mosquito breeding sites).
What is the transmission cycle of malaria? (3)
- Mosquito ingests parasite by feeding on an infected host.
- Parasite grows and replicates in the mosquito’s gut.
- Passed to new hosts (8-15 sporozoites) via subsequent bites.
What are 2 other transmission routes of malaria?
- Blood transfusions, contaminated needles (rare).
- Intra-uterine (mother to baby)
What are the five Plasmodium species that cause malaria?
- P. falciparum (most severe, 90% of deaths)
- P. vivax, P. ovale, P. malariae (milder forms)
- P. knowlesi (zoonotic, affects monkeys and humans)
What are the main methods for malaria diagnosis? (3)
- Microscopic examination with Giemsa/Wright stain
- Antigen-capture (RDT)
- PCR (LAMP) for strain detectiona
What factors influence susceptibility to malaria? (2)
Protection:
- Genetic traits: Sickle Cell Disease (HbS), β-thalassemia, glucose-6-phosphate dehydrogenase deficiency
- Lack of Duffy antigens on red blood cells (blocks Plasmodium entry)
Risk:
- Pregnancy
- Co-infections (e.g., HIV, helminths, COVID-19)
What is the life cycle of malaria? (7)
- Sporozoite Injection: Mosquito injects sporozoites into the bloodstream.
- Liver Stage: Sporozoites enter liver, where they reproduce asexually (~10 days, asymptomatic).
- Blood Stage: Merozoites are released into the blood, invade RBCs, reproduce asexually, and cause cells to burst—resulting in cyclic fever.
- Gametocyte Formation: Some merozoites become gametocytes, circulating in the blood.
- Mosquito Stage: Another mosquito ingests gametocytes, which mature into gametes and reproduce sexually.
- Oocyst Development: Form ookinetes that burrow into the mosquito gut wall, forming oocysts.
- Transmission Cycle: Oocysts burst, releasing sporozoites to the mosquito’s salivary glands, ready to infect a new host.
What is schizogony in the malaria parasite’s life cycle? (2)
Schizogony: Rapid asexual reproduction; a single P. vivax parasite can produce 250 million merozoites in 14 days
- Drug Challenge: Antimalarial drugs must destroy at least 94% of parasites every 48 hours just to maintain equilibrium, as the parasite multiplies so quickly.
What are the main strategies to stop malaria? (7)
- Vector Control: Targeting mosquitoes through larvicides, insecticides, and nets.
- Genetics: Releasing genetically modified mosquitoes to reduce population.
- Transmission Prevention: Drugs that block the spread from infected individuals.
- Vaccination: Developing vaccines to prevent infection.
- Acute Treatment: Drugs to treat active infections.
- Radical Cure: Drugs to eliminate dormant liver forms (prevent relapse).
- Prophylaxis: Drugs to prevent infection in at-risk individuals.
What are vector control methods for malaria prevention? (4)
1) Targeting Larvae:
- Use larvicides like Methoprene (hormone analogue) to prevent maturation.
- Remove/cover standing water (e.g., drain swamps, use oil films) to eliminate breeding sites.
2) Targeting Adult Mosquitoes:
- Apply insecticides and repellents.
- Use long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS).
3) Sterile Insect Technique (SIT):
- Release sterilized male mosquitoes to reduce population.
4) Incompatible Insect Technique (IIT):
- Release males infected with Wolbachia bacteria to produce infertile offspring.
What are the pros and cons of using DDT and Pyrethrins for malaria control?
DDT:
- Opens voltage-gated Na+ channels in insects, highly selective for mosquitoes.
- Cons: Bio-accumulates in animals (t½ = 6-10 years), causing issues like eggshell thinning in predators (e.g., bald eagles). Restricted to vector control (Stockholm Convention 2004).
Pyrethrins:
- Shorter half-life, safer alternative to DDT.
- Cons: More costly than DDT.
How have mosquitoes developed resistance to insecticides (3), and what is a potential solution?
Resistance Issues: Mosquitoes have developed resistance via:
- Enzyme upregulation (CYP450, GSTe2) to detoxify insecticides.
- Mutations making sodium channels insensitive.
- Thickened leg cuticle reducing insecticide uptake.
Solution: Combining CYP450 inhibitors with LLINs to enhance efficacy.
What are the issues with current insecticides (2), and is there potential for better options?
Current Issues:
- Resistance: Mosquitoes have developed resistance to many insecticide classes (e.g., neonicotinoids, carbamates, organophosphates).
- Environmental Impact: Non-selective toxicity harms beneficial insects like pollinators (e.g., honeybees) and other animals.
Future Potential: Research aims to develop more selective and environmentally friendly insecticides to reduce resistance and minimize ecological damage.
What are the steps involved in the Sterile Insect Technique (SIT)? (5)
- Mass Rearing: Mosquitoes are bred in special facilities.
- Separation and Sterilization: Male and female mosquitoes are separated, and ionizing radiation is used to sterilize the males.
- Release: Sterile male mosquitoes are released into towns or cities.
- Mating Competition: Released sterile males compete with wild males to mate with females.
- Infertile Eggs: Females that mate with sterile males lay infertile eggs, leading to a reduction in the mosquito population and decreased disease transmission.
What is the Incompatible Insect Technique (IIT) and how does it work? (3)
IIT Overview: Males are infected with Wolbachia, a maternally inherited endosymbiotic bacteria.
Mechanism: When these Wolbachia-infected males mate with wild females that lack the same Wolbachia strain, the eggs are rendered infertile due to cytoplasmic incompatibility.
Combination with SIT: Trials combining SIT and IIT have shown success in eliminating mosquito populations
What are genetic approaches to controlling mosquito populations (3), and what concerns do they raise?
Gene Drive Introduction:
- Modified male mosquitoes are released with a gene drive that increases the likelihood of gene inheritance to 99%, rather than the typical 50/50.
CRISPR-Cas9 Utilization:
- This technology is used to insert a defective doublesex gene in offspring, resulting in either infertile females or a population composed solely of males.
Field Trial Effectiveness:
- These methods have shown promise in field trials for reducing mosquito populations.
Ethical Concerns:
- The potential ecological impacts and ethical implications of releasing genetically modified organisms into the wild raise important questions about their use.
What are the challenges in developing a malarial vaccine? (4)
- Species Specificity: It is unlikely that a single vaccine will be effective against all Plasmodium species.
- High Parasite Multiplication: A single parasite can multiply exponentially (10,000 to 40,000 times), making it difficult to generate enough antibodies to eliminate every sporozoite before they reach the liver.
- Immune Evasion: Parasites can hide within host cells, complicating the immune response.
- Lack of Investment: Malaria is often not a priority for Western pharmaceutical companies, affecting research and development.
What are the pharmacological targets in malaria treatment? (4)
Sporozoites: Target the initial infective stage introduced by the mosquito.
Liver Forms: Address the hepatic stage where parasites multiply asymptomatically.
Blood Forms: Focus on the asexual reproduction phase occurring within red blood cells.
Gametocytes: Target the sexual stage to prevent transmission to mosquitoes and break the cycle.
What are most vaccine efforts aimed at targeting?
Most vaccine efforts are aimed at targeting the infectious stage—specifically, the sporozoites introduced into the body by mosquito bites.
