Lecture 7. Apicomplexan Parasites; Malaria Flashcards
What are apicomplexa parasites?
Eukaryotic
Obligate parasites (have to have a host) - one or multiple hosts depending on species
Extremely important as disease agents
What are examples of apicomplexan parasite disease agents?
Malaria parasites (Plasmodia)
Coccidia (including Toxoplasma gondii and Cryptosporidium)
Piroplasms (Babesia)
What are apical complexes?
Distinctive to apicomplexans
Apical end contains key cellular machinery for host cell invasion
Some apicomplexans are motile and apical complex is essential for movement
What secretory organelles are located within apical complexes?
Micronemes: secrete proteins into host during invasion
Rhoptries: secrete rhoptry proteins into host cell during invasion
Polar rings (comprised of microtubules): where microtubules shoot out
Conoids: Protrude into host cells in response to calcium
Subpellicular membranes enable parasite feeding from host
How do apicomlexans invade host cells?
Conoids protrude into host cells in response to calcium
Rhoptries are secretory organelles releasing rhoptry proteins into host during invasion
Micronemes also secrete proteins into the host cell
A parasitophorus vacuole is formed
The parasite moves into the parasitophorus vacuole
The polar ring is a microtubule organising centre
How many hosts are involved in the apicomplexan life cycle?
Can involve one or more hosts (human or mosquito)
What is the apicomplexan life cycle?
Sexual – gametes fuse to form zygote
Asexual – sporozoites differentiate to form merozoites
Merozoites undergo multiple rounds of replication
Some merozoites differentiate into gamonts
Gamonts differentiate into gametes
What causes Malaria?
Plasmodian apicomplexan parasites
What vectors are necessary for disease transmission?
Mosquitos vectors are necessary for disease transmission (need human and mosquito host)
How much of the world’s population is at risk of malaria?
Half of world’s population at risk – mainly in tropical areas
WHO African Region carries a disproportionately high share of the global malaria burden (95%)
How many deaths and cases of malaria were there in 2021?
247 million cases worldwide
619,000 deaths
What does morbidity refer to?
Refers to having disease or illness
What does mortality refer to?
Refers to dying from disease or illness
What does malaria have an impact on?
Individuals
Families
Communities
Countries
Regions
What does malaria have multiple, interconnected impacts on?
Health
Productivity
Economic
Education
Health services
What is the causative agent of malaria?
Plasmodium species (5 agents)
What is the most virulent specie that results in malaria?
Plasmodium falciparum
What Plasmodium specie infect alongside P. falciparum?
Plasmodium vivax, concurrent infection is not uncommon
What are the 5 Plasmodium spcies that can cause malaria?
Plasmodium falciparum
P. vivax
P. malariae
P. ovale
P. knowlesi (emergent zoonotic - originated in monkeys)
What Plasmodium species results in the majority of malaria morbidity and mortality?
P. falciparum then P. vivax
What is the vector of malaria?
Female Anopheles mosquito
What does the Plasmodium life cycle always involve?
Mammal and female mosquito as hosts
What occurs in the Plasmodium life cycle?
In insects: gametes fuse to form zygote which forms oocyst
In humans: sporozoites differentiate to form merozoites
Merozoites undergo multiple rounds of replication
Some merozoites differentiate into gamonts
Gamonts differentiate into gametes
What happens in the human liver stages (exo-erythrocytic cycle/outside of the blood cycle) of malaria infection?
- Mosquito takes a blood meal (injects sporozoites)
- Liver cell infected within 30-60 minutes
- Infected liver cell and grow schizont, sporozoits differentiate and reproduce into many merozoites (also dormant hypnozoites from)
- Schizont ruptures, releases merozoites into the blood
What happens in the human blood stages (erythrocytic cycle/ blood cycle) of malaria infection?
- Merozoites invade red blood cells (ring shaped merozoite forms)
- Merozoite starts replicating and differentiating, forming a schizont
- Schizont bursts and causes disease
- A few infected red blood cells become gametocytes that are then re-taken up by the mosquito
What happens in the mosquito stages (erythrocytic cycle/ blood cycle) of malaria infection?
- Mosquito takes a blood meal and ingests infected gametocytes
- Gametocytes form into gametes which fuse together in the salivary glands of the mosquito
- Oocyst forms that when ruptured releases the sporozoites that rae injected into the next host
What is asymptomatic malaria?
Circulating parasites but no symptoms
What is uncomplicated malaria?
Nonspecific symptoms
Fever, shaking chills, profuse sweating, headache, nausea, vomiting, diarrhoea, anaemia (caused by red cells popping)
What is complicated malaria?
Same symptoms as uncomplicated malaria but with additional organ damage and anaemia
Associated with hyperparasetemia and increased mortality
Extreme tiredness and fatigue, impaired consciousness, multiple convulsions, difficulty breathing, dark or bloody urine, jaundice (yellowing of the eyes and skin), abnormal bleeding
What causes the intermittent fever associated with malaria to occur at either 48 or 72 hour intervals?
The simultaneous rupture of the infected erythrocytes and the release of antigens and waste products
What are the pathology and clinical manifestations associated with malaria almost exclusively caused by?
The asexual erythrocytic stage parasites
Do the tissue schizonts and gametocytes cause any pathology?
Sometimes can cause little pathology
What causes organ damage and anaemia associated with malaria?
Ruptured erythrocytes
What does malaria have a tendency to do over months or even years?
Relapse or recrudesce
Who is most susceptible to malaria?
Children, pregnant women, unborn children and those living with HIV/AIDS
What does malaria cause a long term impact on?
Health, life chances and economics
What is cerebral malaria?
Often fatal
Extremely high temperature associated with convulsions and coma
Infected erythrocytes adhere to capillary endothelial cells - erythrocyte become knobbly, as a result of parasite proteins exported to the membrane, these bind to ligands on host cells
What is blackwater fever?
Massive lysis of erythrocytes causes high levels of free haemoglobin in the blood and renal failure – The presence of haemoglobin in the urine gives the condition its name.
What can plasmodia adaptations lead to?
Array of hypervariable membrane proteins to switch between and evade immune system
What can human adaptations lead to?
Higher proportions of people lacking Duffy blood group receptor in endemic areas of P.vivax which cannot bind to receptors and invade cells
Several inherited erythrocyte disorders in endemic areas offering protection against infection
E.g Sickle cell anaemia in malarial endemic areas as having heterozygous alleles offers protection from Plasmodia, especially P.vivax
How many var genes are contained in the P. falciparum genome that encode hypervariable P. falciparum erythrocyte membrane protein 1 (PfEMP1)?
60 var genes
During the erythrocytic stage, each parasite expresses one of its var genes at a time
Why does the malaria parasite switch between different var genes during the course of infection?
The parasite is able to evade destruction by host immunity
How long does protective immunity last?
Only as long as a residual population of parasites is present, if the person is completely cured susceptibility returns. (This is the reason most vaccines are ineffective).
What erythrocytes can P. vivax only enter?
Those with genetically determined receptor sites known as Duffy blood groups
Individuals which lack these antigens are refractory
What are a large proportion of the populations in western Africa, Duffy positive or negative?
Duffy negative, accounting for the low levels of P. vivax in west Africa.
What causes sickle cell anaemia?
A glutamic acid residue is in the amino acid sequence of haemoglobin is replaced by a valine which reduces oxygen carrying capacity
What is the average life expectancy for people who possess homozygous alleles for sickle cell anaemia?
Often die before 30
What do people who possess heterozygous alleles for sickle cell anaemia have?
80-95% protection against P. vivax
What are the problems caused by sickle cell anaemia?
Sickled cells tend to get stuck in narrow blood vessels, blocking the flow of blood
Those with disease suffer painful “crises” in their joints and bones, strokes, blindness, or damage to the lungs, kidneys, or heart
What is the WHO criteria for malaria diagnosis?
Fever and presence of parasites
Can be tested by light microscopic examination of a blood smear or a rapid diagnostic test
What treatment is recommended for P. falciparum?
Artemisinin combination therapy (ACT) - artemisinin derivative plus quinine derivation
What treatment is recommended for P. vivax and P. ovale?
Chloroquine unless drug resistance issue in area – then ACT
What is the main vector control for female anopheles?
Widespread insecticide/larvicide
Destruction of breeding grounds
Indoor residual spraying (IRS)
Long-acting insecticide treated bednets (ITN)
Experimental methods in pipeline
What have insecticide-treated bednets (ITNs) been shown to have effects on?
Shown to reduce severe disease and mortality due to malaria in endemic regions
Shown to reduce all-cause mortality by about 20%.
What are the only insecticides approved for use on ITNs?
Pyrethroid insecticides
Very low mammalian toxicity
Highly toxic to insects and have a rapid knock-down effect, even at very low doses
When do ITNs need to be retreated?
Pyrethroids have a high residual effect: they do not rapidly break down unless washed or exposed to sunlight
The need for frequent retreatments (6-12 months) was one of the most difficult barriers to full implementation of ITNs in endemic countries
What can humans use to protect themselves from malaria?
Chemoprotection – Prophylactic dose to travellers to endemic areas
Chemoprevention – Full treatment dose to children and pregnant women, Seasonal (rainy season), Mass drug administration
Vaccines
Treatment of disease
What three ways can drugs used for malaria prophylaxis?
Kill parasites in the liver - casual prophylaxis
Kill asexual parasites in the red blood cells - suppressive prophylaxis
Kill sexual parasites (gametocytes) in red blood cells - gametocytocidal prophylaxis
What is the RTS,S vaccine?
Virus-like particle (VLP) vaccine
Based on the P. falciparum circumsporozoite protein (CSP)
Targets sporozoites injected by mosquito
Three primary doses plus booster
Efficacy 55%
What is the R21 vaccine?
Based on the P. falciparum circumsporozoite protein (CSP)
Three primary doses plus booster
Efficacy 75%
More manufacturing capacity The world’s largest vaccine manufacturer the Serum Institute of India has lined up to
make more than 100 million doses a year – plans to scale up to 200 million doses a year
Compare with 18 million doses of RTS/S
What were the impacts of COVID-19 on the spread of malaria?
Fragile health system capacity overwhelmed
Misdiagnosis as COVID-19 or flu
Decreased funding
Malaria control delivery systems impacted by absenteeism, supply chain disruption and collecting ITNs
What are the experimental approaches to controlling malaria?
Endectocides (systemic insecticides e.g ivermectin)
Sterile insect techniques
CRISPR/CAS9 gene drives
Biocontrol using bacteria or fungi that infect the mosquito and prevent development of the plasmodium
What is sterile insect techniques and why do they not work quit as well in mosquitos?
Irradiated (GM spermless males) are released into the wild, preventing fertilisation in females
Are not as competitive in mating flights
How can CRISPR be used to prevent the spread of malaria?
Genetically altering genes in the population to result in all male off-spring, sterile females or mosquitos resistant to plasmodium parasite
Ethics – concern about release, impact on downstream food net spread to other organisms
