Malaria Flashcards
Recall the taxonomic classification of malaria.
- Phylum: Apicomplexa
- Genus: Plasmodium
- 4 species infect humans:
- P.falciparum, P. vivax, P. ovale, P. malariae (recently a 5th, P. knowlesi)
- Many other species infect animals
Recall the three stages in the life cycle of P. falciparum.
Recall the important aspects of lifecycle and spread.
Malaria disease only occurs in the _____________. Recall the symptoms.
Most malaria deaths are caused by _____________. ______________ also results in significant morbidity, but low mortality.
Relapsing malaria is caused by _____________.
P. vivax
RBC-infected by malaria parasite becomes ____________ ina mechnaism called __________________. This is a process that avoids ___________________.
adhesive
cytoadherence/sequestration
Recall the function of the PfEMP1 molecule.
It is a family of proteins present on the membrane surface of red blood cells (RBCs or erythrocytes) that is responsible for the cytoadherence of parasitised RBCs. There are 60 copies of the gene encoding PfEMP1, and which one is expressed will determine to which receptor in the BV it will bind to. Different tissues are rich in different type of receptors.
Recall the diagram that shows how malaria may persist for a long time.
By switching around the gene encoding for PfEMP1 after immunity clears one type, the malaria parasite is able to persist over a long period of time (recrudescence). It would also affect different tissues of the body.
______ genes encode PfEMPs.
var
How are most var genes “silenced” while allowing just one to be expressed?
Chromosome ends cluster at the nuclear periphery and is in a ‘silent’ heterochromatic state (epigenetic control of transcription). This mechanism involves histone modification - leading to the genes inaccessible to transcription factors. Since most of the var genes are located at the ends, this configuration allows most of the var genes to be silenced together.
On the other hand, a particular localisation is associated with a new histone modification that permits transcription.
How is a var gene selected to be expressed?
Mostly stochastically - randomly enters into the transcriptional active site (pressured into selection - antibody)
Almost all Plasmodium clones express the same var gene, with only a very small proportion expressing another var gene. The ‘switching’ occurs when the individual begins to develop antibodies to the corresponding PfEMP1 is because of the newly introduced selection pressure (due to the presence of specific antibodies) against the prevailing PfEMP1 expressing clone, allowing the parasites expressing a different PfEMP1 to become predominant and the process to repeat itself. This process involves it involves the expressed var gene moving out of the expression site and another var gene moving in.
Recall how malaria parasite generates rapid diversity in var genes.
It involves recombination of different var genes between heterologous chromosomes. This is possible due to the similar architecture of the var genes in the chromosome ends.
Recall an example of exported protein by Plasmodium into RBC cytosol and its role.
KAHRP “knockout” parasites don’t adhere to vascular endothelium
Exported proteins contain a ____________ motif.
a conserved ‘PEXEL’ motif
Recall the tow important sites in protein export in plasmodium infected RBC.
ER and PV membrane
Recall how PEXEL site is cleaved.
Describe the PTEX translocon.
- Key criteria
- Plasmodium specific and in the correct location
- essential to blood stages
- energy source, un-folding mechanism
- binds transiting cargo PEXEL proteins
- Genetic “knock-down” of PTEX components kills parasites
- PTEX inhibitors are an approach to block many essential proteins/processes via the one target
Recall the 3 types of vaccine of malaria.
- Pre-erythrocytic (before the parasite invade/mature in the liver)
- aim to protect against the early stage of malaria infection—the stage at which the parasite enters or matures in an infected person’s liver cells. These vaccines would elicit an immune response that would either prevent infection or attack the infected liver cell if infection does occur.
- Transmission blocking
- seek to interrupt the life cycle of the parasite by inducing antibodies that prevent the parasite from maturing in the mosquito after it takes a blood meal from a vaccinated person. TBV candidates aim to prevent mosquitoes from becoming infected by malaria-causing parasites when they feed on infected people.
- Blood-stage (anti-merozoite)
- target the malaria parasite at its most destructive stage—the rapid replication of the organism in human red blood cells. Blood-stage vaccines do not aim to block all infection. They are expected to decrease the number of parasites in the blood, and in so doing, reduce the severity of disease.
Different plasmodium species prefer ________________.
Different RBCs
P. falciparum is able to infect red blood cells of any age, whereas other species infect only young or old red cells, which are a smaller fraction of the red cell pool.
__________________ have very little time to act on its targets.
Recall the vaccine targets for malaria.
RBC surface is highly ____________.
Recall that malaria parasite undergoes selective pressure at which it can alter receptor-ligand usage.
All of the variants are as capable in proliferating in the RBCs. Note: W2mef switch its use of EBA175 when grown in NA-treated erhytrocyte
What happens if you delete the ligand (EBA175) used by W2mef?
_____________________ is a mechanism of immune evasion for malaria parasite.
___________ and ________ proteins are important targets of inhibitory antibodies for malaria.
Alternate invasion pathway allow parasites to invade via _________________ receptors and to ___________.
Alternate invasion pathway allow parasites to invade via a diverse range of RBC receptors and to avoid immunity
P. falciparum causes infected red cells to ___________ and to _________________________, which blocks blood flow.
P. falciparum causes infected red cells to clump together (rosette) and to stick to endothelial cells lining small blood vessels (sequestration), which blocks blood flow.
Red cell sequestration decreases ___________ and leads to ________, which is responsible for the manifestations of cerebral malaria
Red cell sequestration decreases tissue perfusion and leads to ischemia, which is responsible for the manifestations of cerebral malaria
The switching of PfEMP1 gene is _______________ controlled.
epigenetically
What is PfEMP1 and KHARP and its role in plasmodium binding?
PfEMP1 is the actual protein which binds to endothelial cells through the RBC membrane. KHARP is part of the ‘knob’ protein cluster which directs PfEMP1 to the RBC membrane and anchors (stabilise the attachment) it there to allow binding to the endothelial cells.
What is the main difference between the Plasmodium sporozoite and merozoite?
The sporozoite is the parasite stage injected into the human by the mosquito. The sporozoites make their way to the liver to undergo asexual reproduction. One vaccine targets the sporozoites in this “pre-erythrocytic stage” to prevent liver infection.
The merozoites are released from the infected red blood cells in the erythrocytic phase of the infection cycle. The vaccine that could work at this stage is called the “blood-stage” (anti-merozoite) vaccine. However the merozoite is only outside for a very short period of time after rupture of the infected red blood cell before going on to infect another red blood cell, so the time available for antibodies to work against the merozoites is limited.
