Lecture 16 - Malaria 1 Flashcards Preview

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Flashcards in Lecture 16 - Malaria 1 Deck (51):

Which infectious diseases are in the top 20 causes of mortality world wide?

What is special about HIV and Malaria?

• Malaria
• Diarrhoeal diseases
• Tuberculosis

HIV and Malaria are important because they are caused by a single pathogen.


What is the phylum and genus of Malaria parasite?
Give some features of the phylum

Phylum: Apicomplexa
• Lot of parasites that belong to this phylum: Toxoplasmodium
• Common feature: single cell, polar
• Apical and distal end
• Apical complex is important for the invasion of the host cells
• All apicomplexans infect other cells

Genus: Plasmodium


Why is Malaria an 'ancient problem'?

• Malaria has been infecting humans for millennia
• The parasite has co-evolved w/ humans


What percent of people on earth will get Malaria this year?
What is significant about this?


This is an incredible selective pressure:
• eg. gene for sickled cell anaemia
• Heterozygotes for sickled cell anaemia are resistant to malaria
• This disease leads to people dying young, but it is less severe than Malaria.


Why was the discovery of the transmission of Malaria important?

Seasonal malaria transmission was endemic in the US, the UK, Italy, much of Europe (every summer)

Once the transmission was uncovered, people in these countries could change their behaviour to prevent transmission
• Removal of water around the house, where mosquitoes were breeding was enough to prevent transmission

NB This was not enough in other countries


What are the four species of Plasmodium that infect humans?

• P. falciparum
• P. vivax
• P. ovale
• P. malariae


Which three tissues can Plasmodium infect?
What is different about the pathogen at this time?

• The insect
• The liver
• Erythrocytes

It is the same pathogen, i.e. the DNA is the same, however there are morphological differences in the parasite.


Where are most deaths due to Malaria?

Equatorial Africa

• Papua New Guinea
• Myanmar


What is seen in South America?

High levels of disease, but less burden of death.
This is because P. vivax is the main species in this area
This species is less fatal


How many cases of Malaria per year in the world?

How many deaths?

300-500 million cases per year

1 million deaths per year


Describe the economic impact of Malaria

Financial burden:
• Bed nets
• Work and School absenteeism
• Represents 10% of annual spending in Africa


What is the vector of the malaria parasite?

Anopholes mosquito


List the stages of the life cycle of the malaria parasite
What type of reproduction is occurring at each stage?

1. Mosquito stage
• Sexual reproduction

2. Liver stage
• Asexual reproduction

3. Blood stage


How is malaria infection diagnosed?

Haemozoan crystals seen on a blood smear

• Haem in the haemoglobin is toxic to the parasite
• The parasite crystallises the haem into Haemozoan
• Gold particulate crystals visible


What are sporozoites?

• Haploid
• Generated by meiosis (sexual reproduction) in the mosquito
• This is what infects the humans


How does the parasite get into the human host?

• Mosquito vector takes a blood meal in humans
• Saliva is injected to prevent the blood from clotting
• Parasite present in the saliva


Describe the initial stages of infection in the human host

1. Sporozoite circulates to the liver
2. Moves through Kupffer cells into hepatocytes
3. Resides in a hepatocyte and replicates asexually
- can be one parasite, or could be up to 100 -
4. Emerges from the liver as a Merozoite

NB No disease or clinical syndrome is observed at this point because the numbers are too low.


Differentiate between a merozoite and a sporozoite

Sporozoite: haploid parasite from sexual reproduction in the mosquito

Merozoite: emerges from replication in the liver cells


Describe the later stages of the life cycle

1. Merozoites emerge from hepatocytes into blood
2. Infect RBCs
3. Amplification, eat up the haemoglobin
4. Burst out of the RBC
5. Infect more RBCs
• initially: 1000 RBCs infected → 10^11


What percent of a person's RBCs can be infected by the parasite?

1% - 10% of all RBCs can be infected in a patient w/ malaria


How long does it take after for the parasites to infect hepatocytes after entering the body?

30 mins


How long does the sexual stage in the Anopheles mosquito last?

1-2 weeks


How long does the asexual liver stage last?

1-2 weeks


How long does the asexual blood stage last?
Characterise it

2-3 days

It is relatively synchronous: all parasites are bursting out of the erythrocytes at the same time:
• Within an hour or so, within a 48 hour cycle


When does disease occur after parasite infection?
Describe the fever in malaria

A week to a month

Periodic fever is observed:
• Every time the parasite burst out (release of merozoites), there is release of other compounds from these infected RBCs.
• This causes a cytokine storm
• This is what drives the periodic fevers


Describe how the parasite gets back into the Anopheles mosquito

1. Gametocytes are produced in the blood

2. Another feeding mosquito takes the gametocytes up


What is a very important parasite protein?



In which stage of the lifecycle is disease observed?

In the blood stage


What are the symptoms of malaria?

• Fever
• Chills
• Anaemia


Which parasite species accounts for most deaths?
What pathologies are caused by this species?

Compare this with another species.

P. falciparum accounts for 95% of deaths
• Cerebral malaria, coma
• Severe anaemia
• Placental malaria

P. vivax causes significant morbidity, but low mortality


Which parasite species causes relapsing malaria?

When was this often seen?

Why does this pose a significant problem?

P. vivax

• Returning soldiers kept on getting Malaria
• Unique characteristic of P. vivax: latent form in the liver (hypnozoite)
• Periodically the parasite will reactivate, come out to the blood, replicate and cause disease

This poses a great problem to the eradication of malaria, because the parasite is remaining latent in half a billion people


What are hypnozoites?

Latent P. vivax in the liver


What is the role of the spleen in RBC regulation?

How is the process subverted in malaria?

• RBCs pass frequently through fenestrations in the spleen
• The spleen detects whether or not they are healthy
• If not, they are taken out of circulation and destroyed

Cytoadherence / sequestration:
• In malaria, the infected erythrocytes adhere to the walls of the microvasculature
• They never go through the spleen


What is one of the biggest factors leading to mortality in malaria?

Cerebral malaria:
• Cytoadherence of the parasite to the microvasculature in the brain


Describe the sequelae of cytoadherence

Leads to severe disease in particular tissues

Cerebral malaria:
• Adherence of the parasites to vasculature in the brain
• There is an enormous biomass of parasites.
• We don't know how this leads to coma and death, however, it is one of the biggest factors leading to mortality in malaria
• Not direct ischemic damage (as in a stroke)


List some of the various organs in the body that the parasites might adhere to

• Cerebral microvasculature
• Placenta: blood vessels
• Adipose blood vessels
• Skeletal muscle
• Kidney


Describe how malaria parasites cytoadhere

• Protein on the parasite sticking out from the surface of an infected RBC
• An adherence ligand
• Binds to receptors on endothelial cells:
- CD36; endothelial cells
- ICAM-1; esp. cerebral malaria
- chondroitin sulfate A; placental malaria


Describe the levels of parasite in a patient over time

• High parasite load
• Decrease in parasite load
• Increases again

Due to
• Antigenic variation
• Antibodies are made, infection is almost cleared
• Then the infection comes back, because of antigenic variation in PfEMP1
• The whole population of parasites switches the type of PfEMP1
• The antibodies are no longer neutralising, and another response must be launched


Describe the various pathological consequences of switching of PfEMP1 type

The pathological consequence:
• The various antigenic forms of PfEMP1 also have different adherence phenotypes:
• Some like sticking to ICAM-1
• Some to CD36: skeletal muscle, low morbidity

It is a roulette wheel, as to whether the parasite switches to a very virulent form of PfEMP1, or a milder form


Describe the mechanism of PfEMP1 switching

• var genes encode the PfEMPs
• There are more than 60 copies per genome
• Only one is expressed at any one time
• The other 50 are kept silent through epigenetic modifications

• In an infection, at some point, one of the parasites will switch its expression
• This parasite will be able to avoid the immune response, and will grow up
• This is where we see the waves of parasitaemia


How many chromosomes in the genome of Plasmodium?
How many copies of PfEMPs per genome?


More than 60 copies per genome


What are var genes?

PfEMP1 genes


Where are the var genes often located on the chromosomes?

Sub-telomeric regions: near the telomeres on the ends of the chromosomes


What is the name for parasites in the blood?



Where will neutralising antibodies against the malaria parasite bind?

Where PfEMP1 binds to the ligand on the vasculature


What is recrudescence?

Persistence of the parasite


Malaria is the ... most common cause of mortality throughout the world



What is the major amplification stage of the P. falciparum life cycle?

The blood stage


What is the gender of the mosquito vector?



Which ligand allows infected RBCs to adhere to the vasculature in the following:
• Placenta
• Brain
• Microvasculature

Placenta: CSA

Brain: ICAM-1

Microvasculature: CD36


Which genes encode the PfEMP1 ligands?

var genes