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Zpath term 2 > Trypanosomes. > Flashcards

Trypanosomes. Flashcards

1
Q

Tryp interactions with the immune system.

A

Evasion of humoral response.
Evasion of innate response.
Modulating the immune system.

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2
Q

Types of tryp

A

T b gambiense (west, chronic), T b rhodesiense (east, acute), T. cruzi.

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3
Q

Tryps - evading the humoral response.

A

T. b. –> Antigenic variation.

T. c. –> sequestration and mucin glycoproteins.

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4
Q

Different forms of HAT

A
  • Slender forms establish parasitaemia

* Stumpy forms are important for transmission.

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5
Q

Evasion of humoral response T. cruzi sequestration.

A

Sequestered inside cells as amastigotes. Released after transformation to bloodstream trypomastigotes.

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6
Q

Evasion of humoral response T cruzi mucin glycoproteins.

A

Over 800 genes coding for these. They accept sialic acid residues. Variable mucins are expressed in the human host, and invariant ones in the vector.

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7
Q

Tryp undulating parasitaemia.

A

VSG changes forces host to mount successive waves of VSG-specific antibodies. Periodic control by antibodies, followed by expansion of different VSG expressing parasites  undulating parasitaemia.

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8
Q

Tryp evasion of the innate immune system.

A

Human trypanolytic factors.
Stumpy cells.
Complement

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9
Q

Human trypanolytic factors

A

Particles
Mechanism
Which are resistant?

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10
Q

Human trypanolytic factors - particles.

A

Pore forming, associates with HDL3 particles targeting endocytic pathway. There are two trypanolytic particles, apolipoprotein L1 (ApoL1) and haptoglobin-related protein.

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11
Q

Human trypanolytic factors - mechanism.

A

Uptake of ApoL1 means entry into endocytic pathway and progressive acidification, leading to its dissociation from LDLs. It then forms pores in the lysosome, and eventually leads to parasite death.

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12
Q

Human trypanolytic factors - resistance.

A

o Gambiense is constitutively resistant to TLF, by unknown mechanism.
o Rhodesiense is inducibly resistant to TLF.

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13
Q

Rhodesiense inducible resistance to TLF.

A

Has SRA protein that interacts with TLF, preventing its trafficking or neutralizing its activity. SRA protein is an truncated VSG in endocytic pathway of parasites. Key determinant is N-terminal helix.

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14
Q

Human trypanolytic factors - T b brucei.

A

Causes nagana in cattle, but not in humans due to TLF.

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15
Q

Human trypanolytic factors - stumpy cells

A

More resistant to antibody dependent complement mediated killing, and are hence prevalent in peak parasitemia.

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16
Q

Complement

A

Consider T. b. and T. c.

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17
Q

T. b. and complement

A

Activate complement, but prevent it proceeding beyond C3 convertase association with the parasite surface.
Rapid turnover of VSG –> rapid turnover of antibodies –> little classical activation.
gp63 important in avoiding lysis.

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18
Q

Turnover of antibodies on surface.

A

Some do recognise VSG –> complement mediated cell killing and act as opsonins. THis is prevented by restriction of accumulation due to endocytosis at flagellar pocket.

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19
Q

T. c. and complement.

A

Regulatory molecules
Calreticulin
gp63 homologues.

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20
Q

T. c. complement regulatory molecules.

A

Complement regulatory protein binds components C3b and C4b and so prevent assembly of active convertase.

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21
Q

T.c. calreticulin.

A

Prevents activation of classical pathway. Binds C1q preventing antibody binding.

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22
Q

Modulating the immune system

A 
T. b:
Trypanokines
Molecular decoys
Supression of T and B cell responses. 
T.c.
Elevate IL-10
Autoimmunity.
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23
Q

T.b. trypanokines.

A

TLTF interacts with CD8 molecule on surface of IFNy-secreting cells to induce cytokine production. TLTF only important early in infection, as neutralizing antibodies are then made.

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24
Q

T.b. molecular decoys.

A

Parasite derived molecules divert host response away from those required for parasite elimination.

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25
Q

T.b. suppression of T and B cell responses. CAUSE.

A

Due to suppressor T cells and suppressor macrophages. Macrophages can be classically activated or alternatively activated, surprisingly. Can lead to general immune suppression. Mostly described but not explained.
Defects in antigen processing reported. Decrease in co-stim presentation.

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26
Q

T.b. suppression of T and B cell responses.

A

Cause

Effect.

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27
Q

T.b. suppression of T and B cell responses. EFFECT.

A

o Production of IL-10, IFN-y and TGFB.
o Suppression of lymphocytic proliferation, probably mostly due to suppressive macrophages.
o Polyclonal B cell activation in murine and bovine models.

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28
Q

T. cruzi interactions with the immune system.

A

o Elevated IL-10.

o Autoimmunity

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29
Q

T. cruzi autoimmunity.

A

Severe cardiac pathology. Probably due to crossreactivity of antibodies. E.g. many parasite proteins have a high degree of homology with proteins, so can induce autoimmune responses.

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30
Q

RNA editing in tryps.

A

Structure of mitochondrial genome.
Process.
Result.

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31
Q

RNA editing in tryps. Structure of mitochondrial genome.

A

o 50 maxicircles give rRNA and mRNA precursors

o Thousands of minicircles give guide RNAs which are used in editing.

32
Q

RNA editing in tryps - process. overview

A

Uridine residues are inserted into or deleted from messenger RNA precursors from cryptogenes. Hundreds of editing events can occur, with insertions being 10x more numerous than deletions.

33
Q

RNA editing in trypansomes - process, mechanism.

A

o Guiding editing position. 5’ end of guide has an anchor region which anneals to mRNA.
o Pan-edited mRNAs require many overlapping gRNAs.
o mRNA is cleaved, U is inserted or removed, then mRNA is ligated again.

34
Q

RNA editing in trypanosomes - results.

A

Correcting frameshifts. Inserting start or stop codons. Much of the coding region is inserted this way.

35
Q

Guiding editing position.

A

5’ end of guide has an anchor region which anneals to mRNA. The rest of it partially anneals; uridines in mRNA to be removed bulge out, and adenosines and guanosines which guide insertion of uridines bulge out on the guide RNA. Unpaired purines in gRNA hence specify insertion of Us, and unpaired Us in mRNA are removed.

36
Q

Tryp antigenic variation.

A

General
Silencing
Expression
Generating diversity.

37
Q

VAT

A

variable antigen type

38
Q

Tryp antigenic variation - general.

A

Most express a single VAT. Up to, but usually fewer than 1% of parasites switch VSG to give a different VAT.

39
Q

Selection pressure on VATs.

A

As immune pressure on the first increases, parasites expressing a different VSG have a selective advantage and hence their population expands. Rapid turnover  rapid switching of VSG seen after transcriptional switch. Traditionally growth peaks have been thought to comprise a single VAT, but recent studies suggest at least 15 variants could be expressed.

40
Q

Tryp Ag variation - silencing.

A

o Sub-telomeric promoters and genes are prone to silencing.

o Several powerful mechanisms

41
Q

Tryp Ag variation - silencing mechanisms.

A

RAP1 is a telomerase associated protein which recruits factors leading to hypomethylation and hypoacetylation of silent ES. These can act via long or short range silencing. Use histone deacetylases as in var silencing.

42
Q

Tryp Ag variation - silencing mechanisms. DRUG TARGET.

A

 Interest in druggable targets involved in silencing: at least one deacetylase is a potential target.

43
Q

Tryp Ag variation - expression.

A

Bloodstream expression sites.
RNA pol 1
Active ES.

44
Q

Tryp Ag variation - expression. Bloodstream expression sites.

A

Transcription of VSG from a polycistronic sub-telomeric transcription units known as bloodstream expression sites. These can have various genes, but several have VSG genes. Expression is monallelic.
15 expression sites found so far on diploid and intermediate chromosomes.

45
Q

Tryp Ag variation - expression. Different models for initiation.

A

RNA pol 1 does transcription.
 Model 1: transcription initiated at all ES promoters, but is processive only at a single, active ES.
 Model 2: initiation only occurs at 2 ES, with one being active and the other being preactive.
 RT PCR analysis of a single cell gave results suggesting that model 1 is correct.

46
Q

Tryp antigenic variation - generating diversity.

A

Two ways gene expressed can change.
Large genomic reservoir.
Interstrain mating.

47
Q

Tryp antigenic variation - two ways gene expressed can be changed.

A

In situ activation.

Recombination.

48
Q

Tryp antigenic variation - two ways gene expressed can be changed. In situ activation.

A

Transcriptional switching to change which ES is active. Mechanism not fully understood.

49
Q

Tryp antigenic variation - two ways gene expressed can be changed. Recombination.

A

telomere exchange, duplicative gene conversion, segmental or partial gene conversion, due to inherent instability of subtelomeres. Breaks naturally arise due to replication fork collapse, initiate DNA resection producing ssDNA and triggering a homology search, followed by homologous recombination.
 Conversion requires homology directed DNA strand exchange.

50
Q

Tryp antigenic variation - large genomic reservoir.

A

Pseudogenes throughout. Minichromosomes archive most of VSG genes. Some on intermediate chromosomes and some on megabase chromosomes which comprise diploid genome.

51
Q

Tryp Ag variation recombination - duplicative gene conversion.

A
  • Copies silent VSG into an active ES. Can be copied from silent ES, from telomeres of mini-chromosomes or from sub-telomeric arrays.
  • BIR mechanism using 70 bp repeat regions. Chromosomal internal VSGs use a similar mechanism.
52
Q

Tryp Ag variation recombination - mosaic VSG formation.

A

Rarer than duplicative gene conversion.

• Only part of the gene is recombined in. Often uses part of one or more pseudogenes.

53
Q

Interstrain mating.

A

o Inter-strain mating in tsetse fly salivary glands. Not obligate.

54
Q

Human African Trypanosomiasis prevalence.

A

NTD, highly prevalent in the Tsetse belt across central Africa, with around 7000 cases per year —> high prevalence in rural villages in Angola, DRC and southern Dudan due to civil war causing disruption of health services

55
Q

Tryp vectors

A

Tsetse fly (glossina spp)

56
Q

VSG attachment.

A

GPI anchor.

57
Q

VSG coat properties.

A

Dense nature of VSG prevents access to PM or any other invariant surface epitopes such as ion channels/receptor —> only part of the trypanosome the immune sys can see are the N-term loops of the VSG (millions of identical copies)

58
Q

Antigenic variation and T cell recognition.

A

antigen polymorphism affects T cell recognition more severely, because T cell recognition depends on the primary structure (amino acid sequence) of proteins rather than protein conformation, which is often recognized by antibodies. Substitution of only one amino acid in a protective T cell epitope results in the failure to activate protective T cells

59
Q

R0 for simple vector borne microparasites.

A

R0 = (R0_v to h)(R_0 h to v) = (V/H) a-2b_hb_v/vu_v
The most important factor is a because it is squared. a is biting rate. The longer the vector life expectancy, the higher the prevalence of infection. To take this into account, use p, a longevity factor. Multiply the equation by p-n/ -lnp.
V = density of vectors
H = density of human host
b_h = proportion of infectious bites leading to infection in host.
b_v = ditto leading to infection of vector.
v = per capita rate of recovery of infection
u_v = per capita death rate of vectors.

60
Q

Transmission rate vector to human during the lifespan of a vector.

A 
T_h = (V/H) * a*b_h* (1/u_v)
V/H = constant of density of vectors to host.
a = biting rate
b_h = proportion of infectious bites causing human infection. 
u_v = per capita death rate of vectors.
61
Q

Transmission rate human to vector during the duration of infection in the human.

A 
T_v = a*b_v*(1/v)
a = biting rate
b_v = proportion of bites by susceptible vector causing infection of vector.
v = per capita rate of recovery of humans from infection.
62
Q

Malaria: breakpoint function.

A

Breakpoints function in uptake functions in vectors, in mating probabilities, in aggregation and immunit.
It is the point at which prevalence stops tending to endemicity and starts tending to extinction.

63
Q

Tryp motility development and disease pathogenesis.

A

o Directed migrations necessary to complete developmental transformation into mammalian infectious forms in salivary gland
o Penetration of BBB critical in disease pathogenesis.

64
Q

Motion of tryps

A

Traditional view: auger.

Now thought: waves of alternating handedness propagate along the flagellum.

65
Q

Tryps traditional view.

A

Auger-like fashion with a twisted cell body rotating around its long axis as it moves forward, flagellum tip leading. Flagellum wraps around the cell in left-handed helix. Trypanon = auger, soma = body.

66
Q

Tryps helical waves.

A

Helical waves of alternating handedness propagate along the flagellum and are separated by a distinct topological feature, a kink. Dominant waveform is tip to base (opposite to most organisms). Interrupted intermittently with base-to-tip waveform for re-orientation.

67
Q

Tryps switching of waveform.

A

Switching of beat seems to depend on outer arm dyneins, as loss of these results in loss of dominant beat form, and steady base-to-tip beat that drives cel movement in reverse.

68
Q

Speed of tryp movement.

A

o Highly variable beat parameters.

o 20 um/s

69
Q

Tryp axoneme

A

9 outer doublet microtubules surround a central pair apparatus of singlet microtubules.
Outer doublets have complete A tubule and incomplete B tubule. Outer and inner-arm dyneins extend from each A tubule, and provide the driving force for motility. Little is known about individual dyneins.

70
Q

Trypanosome paraflagellar rod.

A

Paracrystalline filament made of PFR1 and PFR2 that runs parallel to axoneme and is essential for normal motility. Enriched in Ca++ signaling signatures, so may be important in signaling pathways. Possibly acts as a scaffold protein.

71
Q

Regulation of tryp motility

A

 Outer arm dynein motors: direction.
 Control of dynein motors.
Partially mediated by dynein regulatory complex
 MAPK appears important – many seem to phosphorylate flagellar structures such as the basal body.
 Kinesin motors for PFR assembly and control of motility.

72
Q

Tryp motility on surfaces

A

T. brucei on semisolid agarose surface  social motility, where parasites assemble into multicellular communities. 2008. More complexity than first understood.

73
Q

Other roles for tryp flagellum.

A

Considered to alter access to flagellar pocket.

74
Q

Flagellar pocket.

A

Although the flagellar pocket is not completely membrane enclosed, electron-dense adhesion zones hold the flagellum in tight apposition to the cell membrane and demarcate the boundary of the flagellar pocket membrane (Figure 2f), causing a constriction termed the flagellar pocket neck or collar (14, 51). Hence, the lumen of the flagellar pocket is effectively an extracellular compartment that is secluded from hostile host environments.

75
Q

Tryp cruzi host cell entry

A

Infection with metacyclic trypomastigotes —> invade macrophages to become amastigotes (primary host cell = macrophage, but probably all mammalian nucleated cell types susceptible to infection).
Invasion = parasite-specified phagocytosis —> escape of phagocytic vacuole - unknown whether motility (flagella) plays role in invasion process.
Entry into non-phagocytes involves the formation of a tight membrane-bounded vacuole around trypomastigote —> might originate from intracellular organelles seems to be actin independent.

76
Q

T. cruzi and sialic acid

A

When trypomastigotes of T. cruzi emerge from cells of the mammalian host, they contain little or no sialic acids on their surfaces —> express a unique cell surface trans-sialidase activity —> specifically transfers α(2–3)-linked sialic acid from extrinsic host-derived macromolecules to mucin-like protein —l Abs block invasion.

77
Q

Initial binding of T. cruzi.

A

attachment of T. cruzi to host cells appears to require not only an immediate availability of specific surface molecules, but ATP-dependent processes as well —> energy need perhaps for rearrangement of surface mols/secretion.
Several metacyclic surface mols implicated in invasion including gp90 and fp82.

Zpath term 2 (14 decks)

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