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Parasitology and entomology > Malaria > Flashcards

Malaria Flashcards

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1
Q

Where is emerging resistance to artemisinin reported? Why could this be catastrophic?

A

Cambodia. If resistance to artemisinin spreads throughout Africa, where artemisinin is the first-line treatment, this could be catastrophic.

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2
Q

What is the main cause of pathology in malaria? What is released at this stage that are classed as “toxins”?

A

The eruption of malarial parasites (merosomes/merozoites) from the erythrocytes, causing fever and pathology due to toxins being released (GPI, haemozoin, and parasite DNA).

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3
Q

What are malaria fevers called and why?

A

Tertian fevers because of the cyclic lysis of RBC which occurs every 2-3 days.

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4
Q

How can inflammation be pathogenic?

A

If pro-inflammatory cytokines are produced in response to malarial toxins in excess, pathology can occur- we need regulation of this response to be beneficial and not cause pathologic inflammatory responses e.g. a cytokine storm.

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5
Q

Describe the process leading to a cytokine storm in response to malaria parasites.

A

Infected and uninfected red blood cells travel to the liver where they undergo splenic clearance. This leads to splenic macrophage activation which produces cytokines, leading to a cytokine storm if unregulated.

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6
Q

What are the regulatory cytokines that may help “calm” the cytokine storm?

A

IL10 and TGFß are regulatory cytokines produced by T regulatory cells.

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7
Q

What is the function of PfEMP1 and which genes are they encoded by?

A

Encoded by VAR genes.
They enable sequestration and rosetting which build up in cerebral microvasculature and contribute to cerebral malaria. Rosetting also allows immune evasion by sticking to uninfected RBC to protect from immune detection.

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8
Q

How is the sticking of uninfected red blood cells mediated by infected RBC?

A

Mediation occurs through the complement receptor.

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9
Q

What are the usual outcomes of pregnancy-associated malaria?

A
  • Placental insufficiency (inability of the placenta to provide oxygen and nutrients to the baby).
  • Low birth weight
  • Premature birth
  • Possibility of still birth/ foetus abortion.
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10
Q

What are the general features of cerebral malaria?

A

Features may differ between African and Asian populations however:

  • Odd posturing (from cerebral disruption/ brain damage)
  • 15-20% mortality (HIGH).
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11
Q

What mediates the sequestration of infected RBC to the cerebral microvasculature?

A

EMP1 proteins bind to ICAM (intracellular adhesion molecule) or endothelial protein receptor in the brain e.g. endothelial protein C receptor (EPCR). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404108/

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12
Q

What is the significance of chondrotin sulfate A in malaria?

A

Chondrotin sulphate A is ONLY found in pregnant women and binds VAR2CSA (a PfEMP). This blocks transplacental nutrients.

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13
Q

What is the role for inflammatory cytokines in cerebral malaria?

A

Patients who died of cerebral malaria had very high TNF alpha levels- this cytokine signals for apoptosis and nectosis

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14
Q

Malarial anaemia can be silent or acute. What are the main causes of malarial anaemia?

A

NOT predominantly because of RBC lysis (low number of cells contain parasites). RBC loss is mainly due to the phagocytosis of both infected and uninfected cells by macrophages in the blood but mainly in the spleen (splenic clearance)

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15
Q

How many RBC are lost per iRBC?

A

12 RBC per iRBC.

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16
Q

In malarial anaemia, erythropoiesis is inhibited. What are the factors that cause this?

A
  • Haemozoin (by causing apoptosis of erythroblasts and erythroid precursors)
  • Increased levels of TNF alpha and IFN gamma
  • MIF (macrophage migration inhibitory factor)

-These factors suppress bone marrow erythropoiesis.

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17
Q

What conditions/ genes are protective against malaria?

A
  • Sickle cell
  • Blood group O reduces rosetting and so may be protective against severe cerebral malaria
  • Mutations in the glycophorin genes may also decrease risk of malaria by 40%.
  • HBC haemoglobin variant inhibits actin filaments in parasites necessary for metabolism.
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18
Q

Where else is chondrotin sulphate A highly expressed and how was this used medically?

A

Also highly expressed in cancer (as well as in pregnancy) so tried to target using a VAR2CSA vaccine.

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19
Q

Which antimalarial drugs were synthesised using the quinline nucleus

A

Chloroquine and mefloqine

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20
Q

What are liver schizonticides and what kind of drug are they?

A

They target the liver stages and are considered prophylaxis as they are killed inside the hepatocyte before they emerge and cause symptoms.

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21
Q

What is causal and suppressive prophylaxis?

A

Causal prophylaxis- killing parasites inside the hepatocytes before they emerge
Suppressive prophylaxis- killing parasites after they have emerged from the liver to try and entered the erythrocytic stage

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22
Q

What is a radical cure?

A

Targeting the hypnozoites and the dormant liver stage.

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23
Q

What are blood schizonticides and what kind of drugs are they?

A

Drugs targeting erythrocytic stage where we already have malaria. These are treatments not prophylaxis.

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24
Q

What is the purpose of gametocytocides? How are these helpful?

A

Preventing the onwards transmission of gametocytes into the female mosquito during blood feeding- hopes to interfere with the transmission process.

Doesn’t help the individual however may protect the community.

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25
What are sporonticides?
Drugs that kill the mosquito infective stages however we don't currently have any drugs that do this.
26
What are the targets of antimalarial drugs?
- Apicoplast - Dihydropteroate synthase and dihydrofolate reductase - Mitochondria
27
How do quinilines such as chloroquine target malaria and how do parasites gain resistance
Mechanism of action: Crosses apicoplast membrane and acidic pH inside protonates 2 groups which traps it inside the vacuole where it accumulates. Inhibits detoxification of haem which builds up to toxic levels and kills the parasite. Malarial resistance: Mutation of lysine 76 in the PfCRT efflux pump allows the drug to enter the channel to be effluxed. PfMDR modulates resistance and is a channel oriented in the opposite direction (this one points INWARDS to vacuole) and hence mutations prevent the drug from entering the apicoplast.
28
How did chloroquine resistance arise?
Was being used in combination with DDT (insecticide). Not very effective in some cases. In brazil, they tried putting chloroquine in table salt as it is tasteless however this exposure of parasites to suboptimal doses produced resistance.
29
How do antifolates target malaria and how do parasites become resistant?
Target: Dihydropteroate synthase and dihydrofolate reductase. These are essential for producing deoxythymidine monophosphate (dTMP) required for DNA synthesis. Sulfonamide (drug) targets the former enzyme by mimicking PABA. Promethamine (drug) mimics the dihydrofolate substrate and binds much more strongly. These drugs are synergistic. Resistance: Mutations of the enzymes provide resistance. Point mutations make the target insensitive to the drug i.e. mutating the target changes their affinity for the drug and makes the drug less effective. Cumulative mutations make the target less and less sensitive to the drug.
30
How do artemisinins target malaria and how do parasites become resistant?
Mechanism: Fe II from haemoglobin breakdown activates the artemisinin by breaking the 7 membered endoperoxide bridge causing the artemisinin to bind to and inhibit proteins and other biomolecules. Resistance: Mutations in kelch13 protein allows the ring stage parasite to persist for longer (extends the ring stage) and accelerates the trophoziote stage. This reduces the time that Fe II from the trophoziote stage can activate the artemisinin (as Fe II is produced during the haemoglobin breakdown in the trophoziote). This is thought to be a stress response to the pulsing exposure of artemisinin
31
How do sulfonamide drugs work?
Are antifolates and mimic PABA, thus blocking the dihydropteroate synthase enzyme.
32
How do drugs such as promethamine work?
Are antifolates and mimic the dihydrofolate reductase and bind to dihydrofolate reductase with a much higher affinity than the natural substrate and hence blocks the activity of this enzyme and folate biosynthesis.
33
What occurs when pyrimethamine and sulfonamide drugs are used together and which stage of disease do they target?
They are synergistic. They target parasitic stages where DNA replication occurs. This includes both liver and blood stages so can be both prophylaxis and treatment.
34
What is the name of the antifolate drug currently in human trials that affects both the resistant and sensitive forms of the folate biosynthesis enzymes?
P218
35
What are the pros and cons of artemisinin?
Pros: - Very potent - Causes parasite load to drop very quickly - Very safe Cons: -Has a very short half-life
36
How do apicoplast drugs target malaria? What is an example of this drug and is there resistance?
Are antibiotics that target the bacterial nature of the apicoplast. Targets things such as the bacterial 30S ribosome which is present in the apicoplast. Is slow-acting and causes a delayed death effect by preventing cellular processes and division in the second generation of the parasite. THis is thought to be through preventing the carryover of functional apicoplasts which prevents normal ribosomal synthesis.
37
Why does vivax have a larger geographical distribution than other species?
It can persist inside mosquitoes at lower temperatures, thus expanding its geographical range.
38
How do quinolones target malaria and does resistance arise?
The only quinolone used to treat malaria is atovaquone. It targets mitochondrial function by inhibiting the cytochrome B-C complex so that the electron transport chain is inhibited. This causes the collapse of electro potentials at the inner mitochondrial membrane. High-level resistance is produced by single amino acid polymorphisms e.g. from tyrosine to guanine.
39
What is the usual treatment used when a malaria is identified as not falciparum but the species is not known with certainty? What is the length of this treatment course? What may be added to this course and why?
Use chloroquine or artemisinin combination therapy (ATC). Just ATC may be used in areas of chloroquine resistance. Treatment is 3 days. An additional 14 day treatment with primaquine may be added to clear hypnozoites.
40
Why is spirondalone significant? How does it work?
Was the first novel antimalarial drug produced? It targets the sodium ATPase to disrupt sodium regulation.
41
How does the drug dihydroorotate dehydrogenase work and what are its limitations?
It works by inhibiting DNA synthesis. This could, therefore, be used to target liver-stage parasites. One limitation was discovered when testing in Peru, that only falciparum species were affected and not vivax.
42
Why could using a p knowlesi model be informative?
Pk is phylogenetically closer to the other three species of malaria, whereas Pf is further away and so when testing promising candidates, those that work for Pf often are not effective against other species.
43
What are the species of malaria which are responsible for the most deaths?
Falciparum and vivax. Falciparum causes the most deaths as it is more likely to become cerebral/ complicated malaria whereas vivax is more widespread.
44
Why is vivax less prevalent in Africa?
It requires the Duffy antigen on the surface of RBC for infection of the RBC to occur, the expression of Duffy antigens is lower in Africa.
45
What are the species of P ovale?
Wallakeri and curtisi.
46
What are the periodic cycles of each speices?
``` Pf 48 hr Pk 24 hr Pm 72 hr Pv 48 Po 48 ```
47
What is a condition, other than sickle cell, that confers resistance against cerebral malaria?
Ovalocytosis- a condition where rather than concave RBC, they are elliptical.
48
What are the benefits of rosetting for a plasmodium parsite?
- Evades immune response (e.g. effectors, Ab attack) | - Brings RBC around iRBC so when merozoites are released, can directly infect surrounding RBC.
49
Why is antigenic variation of parasites useful?
Allows the parasites to evade immune recognition and responses. (Evades antibody response of the host).
50
Where does Pf gametocyte development take place? Why is this useful?
Bone marrow. This maturation process takes a long time (up to 10 days) whereas a trophozoite maturing to a schizont occurs 1-2 days. This means the gametocyte is would be exposed to the immune system for longer however residing in the bone marrow allows it to "hide:.
51
Describe the sexual developmental stages of gametocytes once they are taken up by female mosquitoes.
Micro and macro gametocytes mature into gametes which are fertilised to form a zygote. The zygote becomes motile and elongates to form an ookinete. The ookinete invades the midgut wall and forms an oocyst. The oocyst develops and matures and eventually releases sporozoites which travel to the salivary glands.
52
Where is artemisinin resistance emerging and why is this a problem?
It is emerging in SE Asia (and independently also in S America. This is a problem as artemisinin is used as first and second line treatments with artemisinin combination therapy (ACT) being widespread. This could be an even bigger problem if artemisinin resistance spreads to Africa. https://www.who.int/malaria/media/artemisinin_resistance_qa/en/
53
Which species of malaria is artemisinin combination therapy (ACT) recommended for?
Used for uncomplicated falciparum infection as well as for cases of chloroquine resistance in vivax.
54
How do we know that we can have immunity to malaria?
- Mainly children show mortality/ are affected | - Chronic asymptomatic infection in older people/ adults do not get as sick.
55
What is clinical immunity vs antiparasite immunity?
Clinical: ability to tolerate a large parasite burden without clinical symptoms. Anti parasite: control parasite burden below a threshold, above which disease symptoms would be seen.
56
What is required to maintain immunity to malaria?
Constant infection.
57
WHy could immunity in low transmission areas not be achieved?
Not be exposed enough/ enough times for immunity ot be robust enough to be protective.
58
Why do infants in high and low tranmsiision zones have lower rates of malaria?
- Environmental- bundled up so bitten less - Foetal haemoglobin not as good energy source for malaria - Antimalarial antibodies cross the placenta - Anti-malarial antibodies in mothers breast milk - Lack of PABA which is required for parasite growth.
59
Extracellular and intracellular pathogens are targeted by which arms of the immune cell respectively?
B and T cells
60
How do antibodies try to prevent malarial pathology?
- Prevent sequestration of iRBC - Sterically hinder invasion into hepatocutes - Impair sporoziote motility so trap them in the skin and stop them entering blood vessels. - Mediate antibody dependent cellular cytotoxicity (ADCC) (activate T killer cells) - sterically hinder gametocytes joining
61
How do T cells try to help deal with malaria infection?
T cells which are IFNgamma+ and CD4+ activate macrophages to phagocytose iRBC.
62
What is a transmission blocking vaccine?
Causes Ab production in human so when mosquito takes blood meal it can prevent fertilisation of gametes
63
What do CD4+ and CD8+ T cells do in response to malaria to get rid of parasites?
CD4+: help CD8 cells and help B cells produce Abs | CD8+: produce IFN gamma which is toxic to infected hepatocytes
64
How do malaria parsites activate the immune system? I.e. which cytokines to they stimulate?
-IFN gamma -IL12 -IL18 (Pro inflammatory cytokines)
65
What do nartural killer cells and CD4 helper cells do in response to malaria?
Produce IFN gamma
66
What does the engagement of the parastie with the pattern recognition receptor activate/ cause the production of?
IL1, IL6, TNF (PRO INFLAMMATORY) Causes the development of fever and sequestration of parasites and induces local inflammation, causing vascular occlusion and production of toxic radicals and NO.
67
Why/ how are low levels of inflammation beneficial?
- Activates NK cells - Activates CD4 cells to produce IFN gamma to activate macrophages to phagocytose iRBC and produce toxins to kill parasites
68
Why/ how are high levels of inflammation detrimental?
- Fever - Tissue damage - Decreased blood glucose - Increase in adhesive molecule expression on endothelium (sequestration) - INhibits erythropoiesis - Promotes phagocytosis of normal RBC - HIgh IFN gamma anf TNF alpha cause pahtology
69
What are two regulatory cytokines produced by Treg cels?
IL10 and TGF ß
70
Why is it thought that malaria can interfere with the production of acquired immunity?
Reports in the 60s that malaria produced poor response to childhood vaccines.
71
What is the memory response to malaria?
Poor memory response to malaria antigens
72
Why is each malaria infection unique?
The obligatory sexual stage of malaria lifecycle produces high antigenic variation.
73
Describe how not everyone responds the same to malaria infection?
Not everyone produces antibodies for the same antigens of malaria and the level of these responses for each respective antigen responded to is different. aka varying repertoire
74
Although there is a rapid reduction in antibody levels after infection, how do we know antibodies are nevertheless maintained?
There is a BOOSTING of response upon reinfection.
75
Why are vaccines a problem?
Too many malarial antigens | Antigens are variable
76
Describe live attenuated sporoziote vaccine.
Irradiated sporozoites can still invade hepatocytes and reproduce but only a few times before they stop. This is thought to allow the development of sterile immunity (doesn't last very long).
77
Desribe genetically engineered sporoziote vaccine.
Similar to irradiated sporozoite. Genetically engineered sporoziotes to have an abortive liver stage.
78
Describe live sporozoite vaccine
Live sporoziotes given with fluroquine to stop blood stage.
79
Describe the prime-boost vaccine.
Adenovirus expressing malaria antigens and boosted with the vaccinia virus also carrying malaria antigens. GIves good levels of T cells and Abs and is the vaccine of choice against liver stages
80
Describe vaccine using infected RBC
iRBC given at low doses then given a cure- generates protective immune response against blood stages.
81
What is the RTS,S vaccine based on
Circumsporoziote protein of sporoziotes
82
What is the RTS,S vaccine composed of
``` RTS= Middle portion of circumsporozoite protein is made of repeats which provides lots of T cell epitopes. S = hepatitis surface antigen ```
83
Why were 3 doses of RTSS vaccine chosen?
was just as low in effectiveness as 3 but 4 increased risk of febrile seizures also in children increase in meningitis and cerebral malaria

Parasitology and entomology (26 decks)

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