Pathogenesis & Malarial Anaemia Flashcards
Broadly speaking, why doe some individuals, but not others, suffer from severe malaria?
- access to healthcare
- the person
-> age, immune status, genetic differences eg sickle cells, duffy negative)
the parasite (virulence factors)
Why is P. vivax only found in East Africa (Somalia, Ethiopia, Kenya)?
95% of the population lack the Duffy antigen on their RBCs
Vivax uses Duffy to enter RBCs
recent evidence in Madagascar of P. vivax infections in Duffy negative people
– exact mechanisms unclear
– seems inefficient and parasite load is low
– parasite will continue to evolve
Give some information on the Duffy antigen.
aka Duffy Antigen Receptor for Chemokines (DARC)
a glycoprotein expressed on the surface of RBCs, endothelial cells, and epithelial cells
acts as a receptor for chemokines like IL-8 and regulates inflammation by binding and clearing chemokines from the bloodstream
commonly caused by GATA-1 TF binding site mutation in the FY gene promoter
– prevents Duffy expression on RBCs
What is sickle cell disease?
Sickle cell anemia is caused by a mutation in the HBB gene, which encodes the beta-globin subunit of hemoglobin
This mutation leads to the production of hemoglobin S (HbS) instead of normal hemoglobin A (HbA)
When oxygen levels drop, HbS polymerizes, causing RBCs to become rigid, deformed, and “sickle-shaped”
What is the difference between those who carry one or two copies of the HbS gene?
Sickle Cell Trait (heterozygous):
offers significant protection against severe malaria without the severe health complications of sickle cell anaemia
Sickle Cell Anaemia (homozygous):
associated with complications like chronic anemia, vaso-occlusive crises, and organ damage
may still experience some protection from severe malaria, but the health risks associated with sickle cell anemia often outweigh this benefit
How does sickle cell anaemia confer resistance to malaria?
haem is present in a free form in the blood of mice with sickle cell trait
– injecting haem into the blood of normal mice before infecting them with malaria, researchers found mice did not develop disease
humans/animals with the sickle-cell trait have to break down and detoxify misshapen red blood cells their entire lives, phagocytes already in place when the malarial parasite attacks them
Sickled RBCs have altered membrane properties, reducing their ability to adhere to blood vessels and form rosettes, decreasing the risk of vascular blockages and severe complications
Why do those who have sickle cell disease have immunity to P. falciparum specifically?
Other malaria species, like P. vivax, rarely cause severe disease and do not rely on similar cytoadherence mechanisms
– P. vivax primarily infects reticulocytes (young RBCs) and uses the Duffy antigen for entry, processes less affected by HbS
P. falciparum has a high metabolic demand and is more sensitive to environmental stress compared to other malaria species
How do cyclical fevers occur in malaria?
in an RBC, trophozoites mature into schizonts which replicate until the cell burst and schizonts are released into the blood
erythrocyte death is what causes fever
– release of parasite nucelic acid, hemozoin, cell membranes into bloodstream
– recognised by innate immune system
cyclical as replication within and subsequent release from RBCs takes time:
– P. malariae = every 72h
– P. vivax, P. falciparum = every 48h
What cytokine is the main cause of fever in malaria infection?
treatment of cerebral malaria w an anti-TNF mAb reduces fever
but does not reduce malaria mortality and results in greater frequency of long-term neurological defects
fever = useful
How was a CHMI study used to look at differences is gene expression between individuals after infection with malaria?
14 volunteers injected w P. falciparum-infected blood
followed for 7-11 days, blood collected every 2 days
3 sets of people found:
– inflammatory = increased gene expression
– suppressive = decreased gene expression
– unresponsive = no change in gene expression
clinical symptoms also varied and matched transcriptional responses
who would go on to develop severe malaria?
What blood stage does sequestration of iRBCs occur?
mature iRBC stages (pigmented trophozoites –> schizonts)
Where does sequestration of iRBCs occur?
in microvascular beds (small blood vessels) throughout the body
brain, gut, skin, adipose tissue (fat), muscle, heart, lung, liver, kidney, spleen, and placenta
this is a cardinal feature of P. falciparum
How does sequestration relate to severe malaria in P. falciparum infection?
all P. falciparum isolates sequester, yet not all infections end in severe disease
severe malaria only develops in infections w a high parasite burden
– necessary but not sufficient
What is acidosis?
obstruction or anaemia leads to tissue hypoxia and a switch from aerobic to anaerobic glycolysis = build up of lactic acid = reduction in pH of blood
acidosis causes impaired consciousness/coma, respiratory distress, and organ failure
best prognostic factor for fatal outcome
– severe malaria is a metabolic disease
reversal of acidosis is v difficult
– only way is to get rid of the parasites
Why does P. falciparum sequester?
remodelling of RBC membrane = increased cell rigidity
the spleen removes rigid cells (usually old or damaged), so sequestration protects iRBCs from being removed
also, low oxygen environment in post-capillary venules is beneficial to parasite growth
What is cerebral malaria?
sequestration causes brain swelling
swelling has nowhere to go, usually goes down back of neck –> squashes brain stem –> stop breathing
Do host immune cells contribute to severe malaria pathology?
no widespread presence of inflammatory cells such as neutrophils and monocytes at sites of sequestration
limited evidence for monocytes or T cells at sites of brain sequestration in fatal human CM
– pronounced feature in experimental CM mouse model
Do cytokines contribute to severe malaria pathology?
high levels of host inflammatory cytokines may contribute to severe malarial anaemia (SMA)
no evidence they are causal, but host cytokines increase expression of cytoadherence receptors on endothelial cells
– bad situation made worse
What is rosetting?
a process in which P. falciparum-iRBCs bind to uninfected red blood cells (uRBCs) as well as endothelial cells, forming clusters or aggregates
mediated by binding of PfEMP-1 to different receptors
