Malaria evolutionary pressure Flashcards
How many malaria related deaths in 2015?
429,000
How many people were infected with malaria in 2015?
212 million
Malaria is not present in which subtropical/tropical areas?
- Areas without local Anopheles populations
- Deserts
- During cooler seasonal periods
- At high altitudes
- In regions where malaria has been successfully eradicated
Where can malaria be found all year round?
In countries located near the equator
Where is malaria most prevalent?
Sub-saharan africa
Why is malaria not present in the US/ Western Europe?
- Due to the prosperity of the economy
- Due to successful malaria eradication programmes
Why is global warming a threat?
Many regions in which malaria has been eradicated still contain Anopheles species which are capable of transmitting malaria; therefore, climate change may cause malaria to re-infect these areas
In cooler regions which Plasmodium is more common?
Plasmodium vivax, more tolerant to cooler temperatures
Why does malaria impose such a great selection pressure?
As it kills a large fraction of the population before reproductive age
It causes higher fatality in children than adults
This imposes a great selection pressure for any mutations which may confer resistance to malaria as these are more likely to be spread as the adults carrying them reach reproductive age
How many malaria associated deaths in 2015?
429,000
Where are the most haemoglobinopathies seen?
In areas where malaria is endemic
What are haemoglobinopathies?
Haemoglobinopathies are inherited haemoglobin disorders
How does malaria cause death?
- Severe forms of malaria such as placental and cerebral malaria due to the PfEMP1 variants
- Malaria causes death due to the occlusion of blood vessels which is caused by cytoadherence of RBC to endothelial cells, platelet mediated clumping and rosetting of red blood cells
- Cytokine storm
Occlusion of blood vessels can lead to?
- Hypoxia= not enough oxygen reaching the tissues and cells
- Anaerobic glycolysis= a build up of lactic acid
What is the structure of red blood cells?
- Biconcave disks
- Dumbbell shaped with the centre being flattened/depressed
- High surface area to volume ratio
- 8 micrometers in diameter
- Contains haemoglobin
- Flexible
What is the shape of red blood cells?
Biconcave disk
Dumbbell shaped due to a depressed/flattened centre
What is the diameter of red blood cells?
8 micrometers
Why are red blood cells flexible?
To facilitate their movement within tight capillaries
Red blood cells lack?
- Nucleus
- Organelles
- ATP production
- MHC
Red blood cells do not express what on their surfaces?
They do not express MHC
How long do red blood cells live?
90-120 days
What is the erythrocyte membrane made up of?
Spectrins and ankyrins maintain the biconcave shape of the red blood cell
What makes up the RBC cytoskeleton?
Spectrins and ankyrins
Lifespan of red blood cells?
90-120 days
When red blood cells age they?
Loose their shape
Red blood cells are removed by?
Macrophages in the liver and spleen
What is haemoglobin?
A protein which is a transporter of oxygen
Haemoglobin structure?
Made up of 4 polypeptides
Each polypeptide is associated with a haem group
Adult haemoglobin structure?
4 polypeptides
2 alpha and 2 beta polypeptides
What is haem?
A non-protein prosthetic group
A porphyrin ring which contains an iron ion
How many oxygen molecules can a single haemoglobin molecule bind to?
4 oxygen molecules
How many haem groups are associated with a single haemoglobin molecule?
4 haem groups
Haem turns what colour when bound to oxygen?
Red
Where can myoglobin be found?
Tissues
What is myoglobin?
An oxygen acceptor
Myoglobin structure?
Made of a single polypeptide chain which is associated with a single haem group
Main difference between haemoglobin and myoglobin?
Myoglobin is an oxygen acceptor but haemoglobin is an oxygen transporter
Myoglobin has a higher affinity for oxygen
Myoglobin is made of a single polypeptide chain but haemoglobin is made up of four
Myoglobin has a higher?
Affinity for oxygen than haemoglobin
Diving animals have?
Higher concentrations of myoglobin in their tissues which allows them to hold their breath for longer
What are the two states of haemoglobin?
Taut form
Relaxed form
When does haemoglobin form the taut conformation?
- Low pH
- High CO2 concentrations
- Low partial pressure of oxygen
- In the tissues
The taut form of haemoglobin leads to the?
Release of oxygen
When does haemoglobin form the relaxed conformation?
- High pH
- Low CO2 concentrations
- High partial pressure of oxygen
- In the lung
The relaxed form of haemoglobin leads to the?
Uptake of oxygen
Compare affinities of the taut and relaxed haemoglobin forms?
Taut form has low affinity for oxygen
Relaxed form has a high affinity for oxygen
Genes for haemoglobin A chains can be found on which chromosome?
16
Genes for haemoglobin B chain can be found on which chromosome?
11
How many haemoglobin A chain genes are there and what are they called?
2
HBA1 and HBA2
How many genes for B chain of haemoglobin?
A single gene
How many genes for A chain in a cell?
4
How many genes for B chain in a cell?
2
What are the different types of haemoglobin?
HbA
HbA2
HbF
Which form of haemoglobin is the most common in adults?
HbA
Which form of haemoglobin is less common in adults?
HbA2
Which form of haemoglobin is foetal haemoglobin?
HbF
Foetal haemoglobin has a higher affinity for?
Oxygen
HbA2 is made up of which chains?
Alpha 2
Delta 2
HbA is made up of which chains?
Alpha 2
Beta 2
HbF is made up of which chains?
Alpha 2
Gamma 2
Which type of globin chain is required to form every type of haemoglobin?
Alpha globin chain
What are the non-alpha globin chains?
Epsilon, gamma, delta, bea
When is HbF most prevelant?
7 months up until birth
When is foetal haemoglobin replaced by adult haemoglobin?
Within 6 months post-birth
Why does foetal haemoglobin have a higher affinity for oxygen than adult haemoglobin?
To provide the foetus with better access to oxygen in the mother’s bloodstream
What are inherited haemoglobin disorders known as?
Haemoglobinopathies
What are the two main types of haemoglobinopathies?
The main types of haemoglobinopathies include:
- Thalassaemia
- Variant/abnormal haemoglobin
What are the two forms of thalassaemia?
Alpha thalassaemia
Beta thalassaemia
What is thalassaemia?
A haemoglobinopathy
It is when there is reduced production/no production of a specific globin chain
What is beta thalassaemia?
This is when there is reduced or no production of the beta chain
What is major beta thalassaemia?
Both genes of HBB are affected
No beta chain production
What is the impact of beta thalassaemia?
Most foetal haemoglobin is replaced by adult haemoglobin within 6 months post-birth
Will lead to severe anaemia within the first year of life
What is required to survive beta thalassaemia?
Blood transfusions for life
Haemopoietic stem cell transplant in childhood
What could cure beta thalassaemia?
Finding a way of increased foetal haemoglobin production
When is alpha thalassaemia the most severe?
When impacting more than two/all of the alpha haemoglobin chain encoding genes
If all four genes of the alpha chain are impacted?
The foetus is highly unlikely to survive gestation
What are thalassaemia disorders?
Reduced or no production of normal alpha/beta haemoglobin chains
Most common abnormal/variant haemoglobin haemoglobinopathy?
Sickle cell disease
What causes sickle cell disease?
A point mutation in the beta haemoglobin gene of chromosome 11
The point mutation leads to which amino acid substitution?
Glutamate –> Valine
Valine is?
A hydrophobic amino acid
When do the sickle cells form?
Triggered by the taut conformation of haemoglobin which occurs at low pH, high CO2, at low partial pressures of oxygen in the tissues
How does the taut form of haemoglobin cause sickle cells?
The taut form exposes a hydrophobic surface region. Causes haemoglobins to aggregate instead of interacting with the cellular environment. This causes fibres to form and the sickle celled shape
What can sickle cell lead to?
Blood vessel occlusion
Lower oxygen availability
How is sickle cell a self sustained process?
Sickle cells cause blood vessel occlusion which leads to even lower oxygen availability causing more red blood cells to become sickle shaped
What is the variant of haemoglobin which leads to sickle cell called?
HbS
Fibre formation is only formed why which haemoglobin conformation?
Taut form of haemoglobin
Characteristics of sickle cells?
Sickle shaped
Can lead to blood vessel occlusion
Lifespan of 20 days
Sickle cells have a life span of?
20 days
Which genotype protects you from malaria with regards to sickle cell?
Homozygous for sickle cell mutation
Heterozygous for the sickle cell mutation
What is the issue with being homozygous for sickle cell?
Fitness cost
Die of sickle cell
As the heterozygote has an advantage and is being selected for this can be known as?
Heterozygote advantage
Overdominance
How does sickle cell protect from malaria?
- Sickle shape of the red blood cell is less likely to adhere to endothelial cells due to PfEMP1
- Red blood cell intracellular environment is altered
- Lower levels of parasite growth
- Red blood cells have a lifespan of 20 days, the parasite takes 2-3 days to develop in a RBC, more likely that the parasitised RBC will be removed by macrophages
- Parasite mutation decreases
What is the duffy antigen?
This is a chemokine receptor located on the surface of red blood cells
Duffy antigen is involved in?
Chemokine bufferring
The duffy antigen is a receptor for?
Plasmodium vivax and Plasmodium knowlesi
Duffy phenotypes?
Fy a+ b+
Fy a+ b-
Fy a- b+
Fy a- b-
Which genotype is most prevalent in Africa?
Duffy silent allele
Fy a-b-
Which allele protects from Plasmodium vivax/knowlesi infection?
Duffy antigen silent allele
Fy a-b-
Where else can duffy antigen be expressed?
Endothelial cells
In other tissues: Brain, kidney, spleen, heart, lung
Duffy antigen is encoded by a gene known as?
DARC
Individuals homozygous recessive for the Fy silent allele are protected from?
P.vivax and P.knowlesi
Individuals homozygous recessive for the Fy silent allele do not express what on their red blood cells?
Duffy antigen
Individuals homozygous recessive for the Fy silent allele do however express duffy antigen on?
Other tissues where it is normally expressed: brain, lung, liver, kidney, spleen, endothelial cells
How is Duffy antigen expression repressed on red blood cells alone?
Due to a mutation in the promoter for the DARC gene
The GATA transcription factor cannot bind which prevents Duffy antigen expression on red blood cells
As Duffy negative individuals still express Duffy antigen on other cell types?
They have a normal phenotype
There is no negative fitness cost
