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Human Molecular Parasitology > Lecture 7 > Flashcards

Lecture 7 Flashcards

1
Q

What are the three T. brucei sub species?

A

T. brucei brucei; non-human but all mammals
T. bruci gambiense; chronic in human (west africa)
T. brucei rhodesiense; acute in human (east africa)

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2
Q

What is the insect vector?

A

Tsetse fly

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3
Q

What are the two stages in human?

A

Stage 1) Haemo-lymphatic

stage 2) Meningo-encephalitic

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4
Q

What is the difference between brucei and rhodesiense?

A

Virtually indistinguishable except for presence of serum resistance antigen gene

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5
Q

What are the early stage symptoms?

A

Chancre at site of fly bite, swollen lymph nodes, fever, weakness, headache, joint pains, pruritis, night sweats and fever peaks every 10 days

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6
Q

What the symptoms as the paraiste develops in the lymph/blood?

A
  • Early symptoms become more pronounced
  • Anaemia due to autoagglutination of red blood cells
  • Cardiovascular, endrrine and kidney disorders
  • Oedema
  • Spontaneous abortion
  • Overall exhaustion of the immune system I
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7
Q

What happens to the brain in the advanced stage?

A
  • Overproduction of proinflammatory cytokines
  • Cytotoxicity
  • Hypoxia
  • Haemorrhage
  • Fibroid necrosis
  • Accumulation of lymphocytes and plasma cells in inappropriate places
  • Altered gait
  • Neurological changes
  • Altered reflexes
  • Aggression
  • Motor changes
  • Coma
  • Death
  • Additionally organs are affected in the later stage
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8
Q

How is early stage distinguished from late stage?

A

Lumbar puncture to test for parasite in cerebrospinal fluid

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9
Q

What type of immune response is seen in the acute phase?

A

Activation of macrophages to produce nitric oxide (NO) and prostaglandins. Leads to lymphocyte hypo-responsiveness in spleen and bone marrow. TNF α to promote inflammation

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10
Q

What type of immune response is seen in the chronic phase?

A

Immune suppression associated with IL10.

TGFβ to promote counter inflammatory cytokines

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11
Q

What percentage of patients develop to late stage in acute and chronic?

A

acute; 87%

chronic; 7%

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12
Q

What causes different pathologies in rhodesiense infection in different regions?

A
  • Different virulences of trypanosomes

- Different host immune responses in each regions

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13
Q

What starts the immunopathological pathways that lead to brain dysfunction?

A

The trypanosome lytic factor - starts the immune response

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14
Q

What two forms does the paraiste take in the blood?

A

Proliferative; long slender

Quiescent; short stumpy

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15
Q

What causes the transition to the short, stumpy form?

What happens to this form?

A

Stumpy induction factor (SIF)

Will either be taken up in blood meal or die

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16
Q

What happens do the slender forms due to peaks in stumpy numbers?

A

They swap their VSGs; only one VSG is expressed by all parasites in bloodstream at one time

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17
Q

Which surface coat proteins are expressed to infect which host?

A

The VSGs are expressed when human infection (includes metacyclic in tsetse fly for transmission)
The procyclin surface coat is expressed on procyclic and epimastigote in fly

18
Q

How does the parasite alter itself for life in the tsetse fly midgut?

A

Transfers sialic acid onto its GPI anchors to protect from digestion

19
Q

How was antigenic variation first seen?

A

Due to the relapses correlating with fever peaks. Proliferative to quiescent which then start to die; so remaining proliferative swap coats and divide again. Each relapse form produces different antiserum when injected into rabbit.

20
Q

What percentage of the parasite surface is VSG?

A

90% (and 10% of total protein production)

21
Q

How are the VSGs recycled?

A

Antibody binding causes then to move to the flagella pocket, be degraded and then a new VSG moved to the membrane. Entire VSG pool can be recycled in only 12.5 minutes.

22
Q

Which region of the VSG has variation?

A

Most variation in the antibody-bindig region

23
Q

How do the VSG protect other surface proteins?

A

Physically block the antibody reaching them by forming a 12-25nm coat

24
Q

How many VSGs can be expressed by metacyclic form? Bloodstream form?
How often do they switch?

A

~14 - changes every 30 divisions

~1000- changes every 100+ divisions

25
Q

What are ESAGs?

A

Expression site associated genes coding for other genes essential for parasite survival

26
Q

How is VSG showing monoallelic expression?

A

~20 expression sites throughout the genome but only one is active at any given time

27
Q

How is expression of the other sites controlled?

A

As the sites are sub-telomeric, telomere silencing is used.

e.g. high base J levels to knock off RNA pol and binding of RAP1

28
Q

Why can T. brucei brucei not infect humans?

A

Cannot deal with trypanosome lytic factors

29
Q

What are the two TLFs?

A

TLF1; apolipoproteins (APLs;ApoL1)+haptoglobin-related protein (HPR)
TLF2; Shares some componets with TLF1 +IgM+specific lipids

30
Q

How are TLF taken up?

A

Endocytosed by binding to TbHpHbR; a receptor used by the parasite for iron uptake to help parasite grow and resist oxidative burst of macrophages

31
Q

What effect does TLF?

A

Lysosome binds to the endosome carrying TLF and causing chloride ion influx and swelling leading to cell death

32
Q

How is TLF blocked by T. brucei rhodisiense?

A 
SRA gene (truncated VSG in the flagellar pocket)
Retains TLF in the flagellar pocket and stops its endocytosis. 
N-terminus of SRA then interacts with C-terminus of ApoL1; allowing it to be lysed without causing swelling
33
Q

Where is SRA expressed from?

A

It is an ESAG; located in the VSG expression site

34
Q

How does gambiense deal with the TLFs?

A

1) TbHpHbr is mutated, L201S, and cant bind TLF1
2) Cystiene proteases target TLF2
3) TgsGP surface glycoprotein in lysosomal strengthens the membrane and stops swelling

35
Q

What is the main component of african trypanosamiasis treatments?

A

Arsenic

36
Q

What is on the rise in the trypanosomes?

A

Resistance to the drugs

37
Q

What new method is being used to find resistance genes?

A

RNAi screens

38
Q

What therapy was developed by Baral?

A

Engineered ApoL1 with removed SRA domain so is lytic for rhodisiense. Conjuncted with antibody for cryptic epitopes of VSG. Showed curative effects in mice

39
Q

What work has been done by Thomson?

A

Using baboon, who are immune to rhodesiense, TLF to create transgenic livestock that are resistant to animal and human T. brucei

40
Q

What effect does a knockdown of NMT have?

A

Results in avirulence and endocytotic effects

Human Molecular Parasitology (8 decks)

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