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Human Molecular Parasitology > Lecture 3 > Flashcards

Lecture 3 Flashcards

1
Q

Which malaria parasite is associated with most of the mortality?

A

Plasmodium falciparum

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2
Q

What are the two problems in battling malaria?

A

Breakdown in mosquito control and failure of antimalarial drugs

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3
Q

How many clinical cases are there?

How many deaths per year?

A

~300 million

1 million deaths

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4
Q

Who are especially at risk?

A

Children, pregnant women and travellers or migrants

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5
Q

What can occur due to infection?

A
  • Asymptomatic infection
  • Mild malaria; fever
  • Severe malaria; severe anaemia, cerebral malaria, respiratory distress and metabolic acidosis
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6
Q

What can provide protection against malaria?

A

Sickle cell anaemia, thalassemia and G6DP deficiency

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7
Q

What causes the cyclic flu?

A

Merozoites infect red blood cell, enter ring stage and undergo nuclear divsion without cell divsion to form schizont. Rupturing of schzont causes flu; the cycle happens every 48 hours for P. falciparum. Each merozoite released can infect new red blood cell; so each cycle increases number of infected cells by a factor of ~30

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8
Q

What are the other symptoms of malaria?

A

Malarial anaemia, hypoglycemia, acidosis and respiratory distress, coma due to cerebral malaria, renal failure, low birth weight and miscarriage

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9
Q

How does the parasite drive cytoadhesion?

Why?

A

Export parasite proteins, knobs, onto the surface of the red blood cells allowing them to change the shape of the red blood cell and allow binding to endothelial cells.
Thought to stop the red blood cell moving through the spleen. Can occur in the brain and lead to cerebral malaria.

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10
Q

What affect can cytoadhesion have on pregnant women?

A

The knobs can bind carbohydrates in the placenta and affect the foetus. Effect lessens after first pregnancy

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11
Q

What happens to the incidence of the three measures of malaria as age increases?

A

All three decrease
As patients age they still have parasitaemia without clinical attacks or death;if you survive into later life then you have immune response that stops disease but cant clear infection

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12
Q

What is required for clinical immunity to malaria?

A

Repeated infections/ chronic infections as antibody responses can be short lived and hence immunity is lose in a short time without exposure to infection

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13
Q

What happens in the pre-erythrocytic stage?

A

Sporozoites from mosquito bite travel to liver and infect hepatocyte. Each forms shcizont, with several thousand merozoites, which are released to infect red blood cells. Asymptomatic.

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14
Q

What happens in the sexual stage?

A

Merozoites differentiate into gametocytes, rather than shizont, within red blood cell. Gametocytes taken up by mosquito in blood meal and differntiate into gamete in midgut and are fertilised to form a gamete. Gamete form a zygote which becomes a ookinete, which moves into the gut wall for the oocyst to develop. Sporozoites rupture out and travel through haemolymph to reach the salivary gland.

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15
Q

Why are the three stages of the life cycle targeted separately for vaccine development?

A

The parasite is morphologically and antigenically different

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16
Q

What would be the best vaccine target?

A

A fully effective inhibition of the pre-erythrocytic stage, would stop infection , parasitaemia, disease and transmission.

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17
Q

What two arms of immune system could be used to act against the pre-erythrocytic stages?

A

Antibody, e.g. to sporozoite surface protein neutralising movement or invasion of hepatocyte
Cellular, e.g. to infected hepatocyte by T cells reacting to MHCI/II presented parasite peptide

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18
Q

What sporozoite protein has been targeted for the only current vaccine?

A

Circumsporozoite protein

19
Q

Which arm of immune system could be used to act against the sexual stage?

A

Antibody - taken up by mosquito in blood meal

20
Q

What are the aims of the sexual stage vaccines?

What are they targeting?

A

Stop zygote and oocyst formation

Targeting gamete surface protein, ookinete surface proteins and the invasion process

21
Q

At what five points of the asexual stage could the parasite be vulnerable to antibody targeted immune attack?

A

1) Merozoite opsonisation; antibody to merozoite recognised by macrophage and taken up and killed
2) Inhibition of invasion; antibody inhibit invasion
3) Merozoite agglutination; cross link the merozoite’s together
4) Inftected RBC opsonisation; antibody to Knob protein
5) Infected red blood cell agglutination; antibody to knob stops cytoadhesion and RBC travels through spleen and destroyed

22
Q

Outline the work done on passive immunisation in gambia

A

Passive transfer of immunoglobulin of immune adults into non immune children can reduce parasitaemia. Same effect seen in first few months of life of children from immune mothers; due to maternal antibody

23
Q

Which proteins should be targeted to stop merozoite invasion?

A

The apical organellar proteins

24
Q

What are the two main vaccine development pathways?

A

Attenuated parasite; how to deliver?

Parasite antigen; adjuvant, antigen or vector system?

25
Q

What is the role of N-myristoyl transferase (NMT)?

A

Adds a myristate to the N-terminal glycine of protein substrates, allowing them to interact with the membrane and be in the right location to carry out their functions

26
Q

How many substrates are their predicted to be for NMT in P. falciparum?

A

~80

27
Q

What role does the inner membrane complex (IMC) play?

A

Keeps the cell shape rigid and provides the power that drives motility, allowing invasion into red blood cells

28
Q

What is process essential for correct IMC formation?

A

Myristation of several proteins found in the complex

29
Q

How does the IMC form?

How was this shown?

A

Begins as a ring around the apical complex and then spreads to cover the entire structure that will become the free merozoite
Tagging GAP45, a component of the IMC, with GFP and following its movement over time

30
Q

What effect does removing the N-teminal glycine from some IMC components have?
How was this shown?

A

The protein no longer part of IMC and is in the cytoplasm
WIth three proteins; Tab5B, GAP45 and CDPK1. Label with GFP and then change the n-terminal glycine and visualise no longer localised in the IMC. Also use western show that when the glycine is replaced the proteins become soluble.

31
Q

What other modification is added to GAP45?

A

Palmitoylation; addition of palmitic acid. Site is N-terminal cysteine residue

32
Q

What is the hypothesis behind using NMT inhibitors?

A

Small molecule inhibitors of NMT will kill the parasite by interfering with one or more essential pathways

33
Q

What are the pro’s of using NMT inhibitors?

A
  • Conditional knock down in the rodent parasite Plasmodium berghei; reduction of NMT results in dramatic reduction in parasite variability
  • Crystal stricture of Plasmodium enzyme and a variety of inhibitors has been obtained
34
Q

What are the cons of using NMT inhibitors?

A

Selectivity over host enzyme may be an issue

35
Q

What are the goals of the NMT inhibitor research?

A
  • Identify N-myristoylated proteins
  • Identify inhibitors of NMT
  • Assess ability of inhibitors to kill parasite
  • Show on target-specificity
36
Q

How can you find out which proteins are being myristated?

A

Use myristate analogue YnMyr, whcih is added in place of myristate and has an alkyne group which reacts with azedo groups. These azedo groups can be tagged with florescent reporter and biotin group. Reaction between azedo and alkyne would never normal happen in biology so very specific. Can pull out protein by biotin tag; then use fluorescence to detect them or use mass spec to discover protein identitye

37
Q

What two types of proteins are myristoylated in plasmodium?

A

Ones with myristoyl added to N-terminus and proteins with GPI anchors

38
Q

How to GPI anchors work?

A

Have glycosylphosphatidylinositol at their C-terminus which holds the protein in the membrane. In plasmodium a myristol group is also found in the anchor.

39
Q

What acitivites are carried out by myristoylated proteins in plasmodium?

A
  • Hydrolyase
  • Receptor
  • Lipid binding
  • Proteolysis
  • Phosphatase
  • Kinase
  • Transport
40
Q

What are ISPs?

A

IMC subcompartment proteins

41
Q

How have the ISPs been shown the be important for differentiation in the sexual stage?

A

Appear to drive protuberance during ookinete development

42
Q

What two approaches have been used to investigate possible NMT inhibitors?

A

1) High throughput screening of compound collections

2) Piggy-backing on earlier work on funal and trypanosome NMT inhibitors

43
Q

What is the IC50?

A

Concentration of the drug that inhibits the enzyme by 50%

44
Q

How have inhibitors been shown to work?

A

Inhibition of YnMyr incorporation
Causes solubilisation of GFP labelled proteins
NMT inhibitors kills malaria parasites in culture

Human Molecular Parasitology (8 decks)

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