Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Parasites and infectious disease > week 3 - chagas disease > Flashcards

week 3 - chagas disease Flashcards

1
Q

what is chagas disease also known as?

A

american trypanosomiasis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what is the distribution of chagas disease?

A

18 countries in latin america

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

how many people are at risk?

A

120 million

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

how many people are currently infected?

A

8-10 million

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

how many deaths are there per year?

A

10-20,000

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

chagas disease was first described when?

A

1909

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

who described chagas disease?

A

carlos chagas put together the whole life cycle of the parasite before he knew it caused chagas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what is the causative agent of chagas?

A

trypanosoma cruzi

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what is t.cruzi transmitted by?

A

triatomine bugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

how many different species can transmit the disease?

A

138

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what are the 3 most important vectors of the disease?

A

triatoma infestans
rhodnius prolixus
panstrongylus megistus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

how many life stages of triatomine bugs are there and which can spread chagas?

A

5 - all of them

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

how do triatomine bugs feed and how do they transmit the disease?

A

heamatophagous blood feeding at night

disease transmitted in insect faeces

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

why is this transmission route ineffective?

A

transmission via faeces is inefficient because it requires a lot of contact between human and vector

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

why are there likely to be high levels of contact between human and vector?

A

because of housing, the thatched roofs are an ideal habitat for bugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

the disease is _____ (animal to human transmission)

A

zoonotic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what are the 3 different transmission cycles?

A

sylvatic cycle - monkeys, rodents, armadillos
peri-domicillary cycle - rodents, foxes, bats
domicillary cycle - dogs, cats, guinea pigs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

other than animal to human transmission what are the 4 other routes of transmission?

A

indigestion of contaminated water/food - sugar cane and fruit juice
blood transfusion
organ transplantation
congenital

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what has resulted in problems in southern states of USA and spain / portugal?

A

modern medical practices

population movement

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what are the 3 major forms of t.cruzi? protozoa type

A

epimastigote
trypomastigote
amastigote

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

where is the epimastigote found?

A

common morphology in insect mid-gut

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

explain a bit about the epimastigote form of the protozoan

A 
15-20 micrometres length
flagellated
motile
binary fission
non infectious
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

what are the 2 trypomastigote forms and where are they found?

A

metacyclic trypomastigote - insect to humans
bloodstream form trypomastigote - humans to insects

highly infectious

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

what is quite astonishing about t.cruzi?

A

it can invade any mammalian cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

explain about the amastigote

A

stumpy flagellated non motile intracellular form
divides by binary fission
infectious

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

what is the life cycle of t.cruzi?

A

As triatomine bug takes a blood meal it defecates

bite induces scratching from host

metacyclic trypomastigotes in the faeces enter the host through the bite site or mucosal membrane

metacyclic trypomastigotes invade various mammalian cells near bite site - initial tropism for local macrophages, fibroblasts and other tissues

inside the mammalian cell the parasite transforms into the amastigote form, which divide by binary fission, genetic exchange reported in amastigote stage

intracellular amastigotes transform into BSF trypomastigotes, they burst out the cell entering the blood stream and then infect other cells

BSF trypomastigotes can also be taken up by triatomine bug taking a blood meal

in the mid gut the BSF trypomastigote transforms into epimastigotes, divide by binary fisison

in the hind gut the epimastigotes transform into non dividing metacyclic trypomastigotes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

what are the infective stage of t.cruzi?

A

metacyclic trypomastigote

BSF trypomastigote

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

what are the host cells of t.cruzi?

A

any nucleated cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

what is the site of replication for t.cruzi?

A

the host cell cytoplasm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What changes occur during differentiation from the replicative epimastigote to the infective trypomastigote?

A 
epimastigote = complement sensitive
metacyclic = complement resistant
epimastigote = low CZ activity
metacyclic = high CZ activity
epimastigote = low trans-sialiadse activity
metacyclic = high trans-sialiadse activity
metacyclic = express T-DAF and mucins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

eventually the parasite wants to end up in which part of the cell?

A

cytoplasm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

which host cell receptors are involved in the uptake of the parasite?

A

sugar proteins - heparin and heparin sulphate

extra cellular matrices

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

what is on the surface of the metacyclic trypomastigote?

A

mucin proteins
sites to which the silic acid residues that are found on the surface of the cell are transferred to the mucin

basically the parasite coats itself with sugar

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

what is the molecule that makes the metacyclic infectious cell resistant to complement?

A

T-DAF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

innate immune mechanisms

A
  • In the complement cascade in the blood you have the C3 componenet of the cascade and when this binds to the cell membrane of a foreign cell it will fragment into 2 components: C3b and C3a, the B component will then recruit a complement back to C3b and this structure will recruit back to complement D to form C3 convertase. So basically the D acts on the B to process it, and we end up with the C3 convertase. This is a protease.
  • That protease (C3 convertase) one of its jobs is then to act on C3 to speed up this break down. So its an amplification process. Eventually recognising something that shouldn’t be there.

Slide
• Now the C3b component is actually recognised by acidic cells and macrophages will come and bind to anything that is not the C3b cell and take it up by phagocytosis.
• The C3a component promotes inflammatory responses.

Slide
• The C3 convertase in addition to promoting amplification cycle will also convert more C3b so you end up with the C5 convertase which then acts on C5 to break it down and process it to another protease, this acts as a marker and a recruiter for the membrane attack complex. This punches a hole through the membrane of the infectious agent and destroys the osmolarity of the parasite.
• That is the whole aim of the complement cascade.

Slide
• On the parasite there is …which essentially binds out most of the C3b and can then be used to get into the macrophages via interactions with the macrophage cell surface, this is how the parasite gets into macrophage. Also as a result of this binding that the C3b is no longer able to participate in the alternative complement activation cascade and this gives the parasite a window of opportunity to do what it wants to do.

Slide
• Basically its complement resistant because it can bind out one of the components of that cascade that allows the parasite to then if it so desires to invade non — cells, the initial stage of the invasion process involves the parasite binding to the host receptors.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

what was originally believed about how the parasite entered cells due to its large size?

A

phagocytosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

how did experiments disprove the phagocytosis entry route?

A

However, if you start labelling experiments and labelling different parts of the cell and start looking at markers for phagocytosis they didn’t coincide. So in this particular image in red is the parasite and in green is the phalloidin. What you would have expected if this particular parasite just invaded the mammalian cell and was going into a non phagocytotic cell via phagocytosis the green pattern would be tightly associated and around the parasite.

38
Q

what did people notice about the cytoskeletal structures?

A

the tubules if you use inhibitors of microtubule these blocked parasites invading so it indicated microtubule formation in parasite invasion
• the parasite when in the host cell is associated with the lysosome mebranes.
• The green dots are associated with a lysosomal marker and they are all around the parasites. You have lysosmal membrane being laid down around the parasite

39
Q

how does the parasite enter our cell?

A

• The parasite binds to the host cell surface and some of the molecules that are being implicated include penetrin that binds to heparin and heparin sulphate and also glycoproteins which bind to the extracellular matrix and that causes a tight bond between the parasite and the cell. Cruzipane activity increases and is released by the parasite. This cistine protease acts on a mammalian marker, kiniogen which releases bradykinin which then interacts with bradykinin receptor on the host cell surface. Bradykinin once it is bound with bradykinin receptor will then activate a molecule called phospholipase C which then acts intracellularly. Signal transduction pathway from the parasite to the cytoplasm of the cell.
Slide
• Phospholipase C breaks down phosphatidylinositol to 2 secondary messenger molecules, diacylglycerol and inositol triphosphate (released into the cytoplasm). In response to IT this activates the ER and responds by releasing calcium
• This initial event causes a cytoplasmic increase in a mammalian cell of the calcium level
Slide
• In response to the increase in calcium level you start getting microtubules laid down towards the site where the parasite is bound. Then along the microtubules you get lysosome recruited towards the site of attachment.
• These lysosomes will fuse with the cell membranes at the attachment site releasing their contents.
•
Slide 41
• This is a mechanism that our cells are constantly doing in response to cell damage
• The parasites have exploited this mechanism
• When the lysosomes fuse with the cell membranes they release their contents, and some of these contents contain sphingomyelinase, and this will act on sphingomyelin that is found on the cell surface and convert it to ceramide. This enduces endocytosis at that point
• The parasite is using a pathway that is normally used to repair membranes, some of the enzymes within it towards the site of infection cause break down of part of the cell membrane surface which promotes endocytosis and as a result of this the parasite is pulled into the cell.
• The parasite produces a molecule called Tc-TOX which interacts with the lysosomal membrane and causes that to disrupt releasing the parasite intot he cytoplasm of the host cell.

Slide 46
• The parasite can then undergo cell division resulting in a zoid and amastigote form which can then via binary fission populate out the cell

40
Q

What are the 3 distinct phases of chagas?

A

acute
indeterminate
chronic stage

41
Q

How long does the acute stage last?

A

2-4 months

42
Q

in the acute stage what are the symptoms?

A

generally asymptomatic

43
Q

In the acute stage the site of infection in some cases can be a hall mark sign how?

A

an inflammation response to localised replication of intracellular parasites, the infection is active (parasites are dividing) —
chagomas (skin lesion)
Romanas sign - only when infection occurs via mucous membrane around the eye

44
Q

In the acute stage who are more likely to exhibit symptoms?

A

children

45
Q

in the acute stage which trypomastigotes can be detected?

A

blood stream form but the number declines with time and eventually undetectable after 3-4 months

46
Q

Host immune resonses are able to control infection but not _______ it. ______ causes disease reactivation where there is a ____ ___ ___

A

eliminate
immunosupression
high mortality rate

47
Q

In the indeterminate stage what happens to the parasites in the blood?

A

they disappear from the blood and patients are asymptomatic and may act as a reservoir

48
Q

in the indeterminate stage the patient remains ____ which can cause issues when trying to detect whether the patient is cured

A

seropositive

49
Q

in how many cases the disease doesnt progress to the chronic stage?

A

70%

50
Q

the chronic stage occurs in how many patients?

A

30%

51
Q

in the chronic stage what happens to the parasite?

A

reactivated

52
Q

how many years later than getting the acute stage can reactivation of the parasite occur?

A

40 years

53
Q

what are the main areas affected by the chronic stage of chagas?

A

cardiac and gastrointestinal

54
Q

what happens if you dont get treatment in the chronic stage?

A

fatal

55
Q

in the chronic stage cardiac problems can affect all parts of the heart including??

A

endocardium - innermost layer of tissue that lines chambers of the heart
myocardium - muscular tissue of heart
pericardium - fluid filled sac that surrounds heart

56
Q

in the chronic stage which nerves of the heart are frequently damaged?

A

autonomic ganglia / cardiac nerves

57
Q

what are the 4 cardiac problems in the chronic stage?

A

arrhythmias
conduction defects
cardiomegaly
thrombo embolic events

58
Q

Explain arrhythmias further

A

ECG abnormalities 2 fold higher in seropositive patients vs seronegative persons ie chagas vs non chagas

59
Q

explain conduction defects

A

blockage of blood vessels serving the heart

60
Q

symptoms of arrhythmia and conduction defects include 4?

A

rapid heart rate
light-headedness
dizziness
fainting

61
Q

what is cardiomegaly?

A

progressive enlargement of the heart - hypertrophy / dilation
thinning of the heart wall particularly at the apex leads to aneurism

62
Q

how do you test for cardiomegaly?

A

shine light through the heart

63
Q

what are thrombo-embolic events?

A

blood clots form

can disperse to other sites, embolisms on other organs

64
Q

What does a histopathology look like of an infected heart?

A

there are localised nests of parasites, the nests bursts and the released parasites promote infiltration by host immune cells.
the inflammation associated with inflitration often damage myocardial fibres and extensive fibrosis occurs. connective tissue replaces damaged cardiac tissue

65
Q

Cardiac symptoms in chagas patients correlate with what?

A

fibrosis

66
Q

during the chronic stage there are also ___ ___ problems as well as cardiac issues

A

gastrointestinal

67
Q

which organs are commonly affected with gastrointestinal problems?

A

oesophagus and colon

68
Q

what is dilation of the colon and oesophagus called?

A

megacolon

megaoesophagus

69
Q

If in conjunction cardiac, colon and oesophagus which precedes?

A

megaoesophagus

70
Q

what are the symptoms of megaoesophagus?

A

: clinical symptoms include difficult/painful swallowing, food regurgitation, speech impairment

71
Q

what are the symptoms of megacolon?

A

clinical symptoms include prolonged constipation, pain & constant physical distress

72
Q

Chagas is suspected in patients that…..(2)

A

exhibit symptoms

have epidemiological history of possible exposure

73
Q

how can you detect chagas?

A

x-rays and other imaging techniques to detect enlargement of affected organs (in chronic stage)

74
Q

what are the direct methods of confirming chagas in the lab?

A

microscopy of fresh blood smear

xenodiagnosis

75
Q

what is xenodiagnosis?

A

when you get a bug to bite a person, then leave bug for a while, euthanise bug and see if triatomine has infection with t.cruzi

76
Q

what are some indirect methods of diagnosing chagas?

A

PCR

serological tests - indirect fluorescence assay, indirect heamagglutination

77
Q

Which drugs can be used to treat chagas?

A

nifurtimox

benznidazole

78
Q

what are 3 preventative measures taken against chagas disease?

A

mozquito nets
insecticide sprays
improving housing and sanitary conditions in the rural area

79
Q

what are the 4 initiatives in latino america?

A

Southern Cone initiative (1985)
72% reduction

Chile, Uruguay, 10 Brazilian states,
12 Argentinean provinces free of disease (2001)

2010 – elimination of Chagas disease as public health problem

Initiative of Central American Countries to Interrupt Vectoral and Transfusional Transmission of Chagas Disease (1997)

Initiative of the Andean Countries to Control Vectoral and Transfusional Transmission of Chagas Disease (1997)

Initiative of the Amazon Countries for Surveillance and Control of Chagas Disease (1997)

80
Q

What is nifurtimox?

A

5-nitrofuran prodrug

introduced in 1964

81
Q

how is nifurtimox administered?

A

orally
2-3 tablets per day
treatment lasts 90-120 days

82
Q

what is the half life of nifurtimox?

A

readily taken up by cells. cross blood brain barrier easily, metabolised by liver, 3 hours

83
Q

what are the side effects of nifurtimox? (5)

A 
mutagenic
carcinogenic 
can fail to clear parasitemia
limited efficacy - acute phase only
resistant strains
84
Q

How is nifurtimox uptaken?

A

passive diffusion

85
Q

what is benznidazole?

A

2-nitromidazole prodrug

introduced in 1970s

86
Q

how is benznidazole administered?

A

2 tablets per day
orally
treatment lasts for 30-60 days

87
Q

what is the half life of benznidazole?

A

found equally in plasma and cells - 70% excreted in urine - half life 12 hrs

88
Q

how is benznidazole taken up?

A

passive diffusion

89
Q

what are the side effects of benznidazole? (4)

A

mutagenic
carcinogenic
limited efficacy
resistant strains

90
Q

do adults or children tolerate nifurtimox better?

A

children

91
Q

how does nifurtimox work?

A

• and you get activation of this nitrate group.
• In the parasites t.brucei and t.cruzi these parasites contain an enzyme called a type I nitro reductase, this enzyme is absent from humans
• what wilkinson et al 2008 has demonstrated that the enzyme itself contains FMN and the activity is not affected by oxygen
o at QM weve been looking at a whole raft of disease compounds – 600 – to look for anti parasitic activity so we can exploit this activity
o what we’ve demonstrated is that you can purify these enzymes and do some in vitro work on these enzymes to identify which compounds are metabolised by the enzymes
o taken in vitro this purified enzyme which is held in the parasites mitochondria and use nifurtimox as a substrate for the parasite enzyme and see what is produced
o what happens is this nitrate group undergoes a series of electron reduction events (2) for a hydroxylamine derivative
o this is like an electronic switch
o the nitro group is a vaccum cleaner taking electrons from the furan ring
o the hydroxylamine pushes electrons onto this furan ring
o the ring falls apart / breaks due to the pushing and pulling of electrons
Slide 76
• What weve demonstrated is if you play around the copy number of the gene (it’s a diploid organism) if you make it haploid the nitroreductase those cells become more resistant to the drug
• When you culture the parasite on the nitroreductase they lost one of the alleles that contained the NTR gene
• Loss of activity or reduction of activity leads to resistant
• If you over express this enzyme you make them more susceptible to the drug

Slide 77
• In humans we lack this type I nitroreductase but we are still able to metabolise nifurtimox
• Type II nitroreductase undergoes 1 electron reduction to form a nitro anioin radical
• The enzymes that mdeiate this conversion are ubiquitous in nature
• In an oxygen rich environment the radical can react with oxygen and make the drug
• The oxygen is converted to superoxide
• Which is normally removed by enzymes called superoxide dismutase
• If you have too much SOD the cell undergoes oxidative stress

Slide 80
• The whole basis of using nifurtimox is how the drug as a nitro group is reduced
• This differs between parasites and humans

Parasites and infectious disease (15 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions