Lecture 19 - Tuberculosis Flashcards Preview

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Flashcards in Lecture 19 - Tuberculosis Deck (85):
0

Which bacteria cause TB?

M. tuberculosis
M. bovis

1

How long has tuberculosis been around?
When was it discovered?

Been around for centuries

Discovered in the 1880s

2

What does infection usually present as?

Chronic pneumonia

3

Describe the onset of TB

Insidious

Slow, eventually getting worse and worse

4

What are the symptoms of TB?

- Cough
- Weight loss
- Fever
- Chills

5

Which organs are affected in TB?

Usually lungs

Other organs can be affected:
- lymph nodes
- brain
- bone
- urinary tract

6

Is TB an important disease?

2nd most common infection after HIV
Third of the world infected
8.8 million deaths in 2010

7

Compare 'infection' and 'disease'

Latent infection: immune system is controlling disease
- no symptoms

Disease: bacteria escape the immune response
- symptoms

8

Can TB causing bacteria be drug resistant?
Talk to this

Yes

This year, there have been completely drug resistant strains reported

Resistance occurs through improper treatment with antibiotics

9

Which parts of the world experience the most TB infection?

Southern half of African continent
Russia
Asia
South east asia

10

How many species are there in the Mycobacterium genus?
Are they all pathogens?

There are many
Most are harmless
Some cause disease

11

What does M. tuberculosis cause?
What is the reservoir?

TB
Humans

12

What does T. bovis cause?
What is the reservoir?

TB
animals

13

What does M. ulcerans cause?
What is the reservoir?

Skin ulcers

Environment

14

What does M. leprae cause?
What is the reservoir?

Leprosy

Humans

15

What does MAC cause?
What is the reservoir?

TB-like disease in AIDS patients

Environmental

16

Are M. bovis infections commonly seen?

Not really anymore

Due to pasteurisation of milk

17

What are the oxygen requirements of M. tuberculosis?

Aerobic

18

What are some of the features of M. tuberculosis?

What are these features due to?

Acid fast
Resistant to drying
Resists killing by macrophages
Resistant to common antimicrobials
Slow growing

Due to the unusual cell wall composition

19

Describe the structure of the cell wall of M. tb

Plasma membrane
Peptidoglycan
Arabinogalactam
Mycolic acids
Superficial lipids
LAM: lipoarabinomannam

20

In one word, describe the cell wall of M. tb

Waxy

21

What can't the gram stain be used to visualise M. tuberculosis?

The cell wall is resistant to other dyes

22

How is M. tuberculosis stained?

Ziehl-Nielsen

1. Carbon fuschin (strong dye) added for 10 minutes
2. Every thing is now pink
3. Decolorise with acid-alcohol
4. Only M. tuberculosis retain the pink dye
5. Everything else counter stained with a blue dye

23

How does M. tuberculosis get into us?

1. Infected person has open lung lesion
2. Infected person coughs / sneezes / talks
3. Droplet nuclei released into air and remain for hours
4. Droplet nuclei inhaled

24

Once inhaled, what happens to M. tuberculosis in terms of immune response?

Avoids mucociliary elevator

Taken up by alveolar macropahages

25

Describe the normal innate response when microbes penetrate into the lower respiratory tract (LRT)

1. Microbe binds to PRR / antibody / C'
2. Phagocytosis by alveolar macrophage
3. Phagolysosome formation
4. Degradation
5. Presentation of antigen on MHC II
6. Release of cytokines

26

What are the different types of droplets?
He long does each stay in the air?

Large droplets: not very long

Small droplets: longer

Droplet nuclei: hours; indefinitely

27

Normally, how are microbes broken down in the phagolysosome?

1. Hydrolytic enzymes
2. Reactive oxygen species (ROS)
3. Reactive nitrogen species (NO)

28

Describe the innate responses in the LTR when droplet nuclei penetrate

1. M. tuberculosis binds to PRR
2. Phagocytosis
3a. Bacterium prevents lysosome fusion with the endosome
3b. Produces ammonium to keep the pH in the phagosome high
4. Survival and replication of the bacterium
5. Some degradation --> MHC II presentation
6. Cytokines release

29

What prevents lysosome fusion with the phagosome?

Mycobacterial lipids

30

Which cytokines are released by alveolar macrophages when M. tuberculosis is taken up?

IL-1
IL-8
IL-12
TNF-a

31

What do infected / activated macrophages then do?

1. Migrate to local / hilar lymph node
2. Activate Th cells
3. Skewed response to Th1

32

Which cytokine released by the APC skews Th cells to Th1?

IL-12

33

What does Th1 produce?

IFN-gamma

34

Which T helper cells are induced?

Th1

Th17 to a lesser degree

35

What is the role of Th17?

Neutrophil activation

36

What do the activated CD8+s do?

Return to site of infection

37

What do the cytokines released by Th1 bring about?

TNF-a
IFN-g

• Inflammation
• Tissue damage
• Macrophage activation

38

What symptoms does IL-1 bring about?

Fever

39

What does TNF-a bring about?

Weight loss
Granuloma formation
Death of some infected MFs

40

Which cells go on to form a granuloma?

Monocytes
T lymphocytes
Neutrophils

41

Discuss the role of macrophaes in the immune response to tuberculosis

Where do the cells that form the granuloma come from?
What signals their migration?

Later:
1. Stimulated by Th1, IFN-gamma

2. Macrophages release IL-8, IL-1, TNF-a

3.
• IL-8: neutrophil recruitment
• IL-1: fever
• TNF-alpha: granuloma formation, weight loss

42

What is the structure of a granuloma?

Multinucleate giant cell
Epithelioid cells
T Lymphocytes

43

What is a tubercle?

Another word for a granuloma

44

How do multinucleate cells form?

Fusion of macrophages

45

What is the purpose of a granuloma?

Walls off the infection
Contains the infection in 90% of cases

46

When does latent infection occur?

90% cases
Immune response contains the infection (granuloma, DTH)

47

What is primary TB?

Aka miliary TB - granulomas sembling millet seeds all round the body

Immune system cannot control the infection

Insidious Pneumonia

Dissemination to other organs

48

In which people do we see primary and secondary TB?

Elderly
Young
HIV / immuno compromised

49

What is secondary tuberculosis?
Describe what happens

5-10% of those who could initially control the infection, several years later, symptoms are noticed.

The immune system has weakened and the bacteria can cause disease

1. Caseous necrosis
2. cavitation
3. Enlargement of granulomas
4. Increased immune response
5. Tissue damage

50

What happens in the lung when the bacteria reactivate?

Tubercle formation
Caseous necrosis
Liquefaction
Cavitation

51

What causes the classical symptoms of TB?

Tissue damage
Cytokines: IL-1, TNF-alpha
Enlarged granulomas
Immune response

52

Describe the productive sputum

Contains large amounts of bacilli

54

Describe the Mantoux test
What conclusions can we make form the test?

1. Inject tuberculin: purified TB antigen
2. Active immune response: pre-formed memory T cells
3. Induration

This test does not indicate immunity or disease, only infection

54

Which two tests look for infection, but can't indicate immunity or disease?

Mantoux test
In vitro IFN-g test

55

Describe the in vitro test that is performed

What does this tell us?
What doesn't it tell us?

1. Collect blood sample
2. Add to medium
3. Add TB antigen
4. Incubate
5. Memory T cells will release IFN-g if present
6. Test for IFN-g

Only tells us if there is infection; we can't conclude that there is disease or immunity

56

What test can be performed to identify disease?

- Chest X ray
- acid fast staining of sputum
- culture on enriched medium

57

Is M. tuberculosis easy to culture?

No - since it is very slow growing

It takes up to two months for the colonies to grow

Alternatively, you can use a liquid medium that takes about a week

58

What therapy is given to those with active disease?

Sorter course treatment - 6 months

Four 2 months:
RIPE:
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol

For 4 months :
Rifampicin
Isoniazid

59

What does the R in RIPE stand for?

Rifampin

60

What does the I in RIPE stand for?

Isoniazid

61

What does the P in RIPE stand for?

Pyrazinamide

62

What does the E in RIPE stand for?

Ethambutol

63

How do isoniazid and pyrazinamide work?

Must be activated by mycobacterium before they are active

64

How can Mycobacterium gain resistance to Isoniazid and pyrazinamide?

Mutations in the enzymes that active the drugs

65

What is directly observed treatment?

The patients are watched to make sure all of the antimicrobials are being taken at once

This is vital in preventing evolution of resistance

66

Which people should be screened for TB?

Children
Immuno compromised
People in contact

67

What is TST?

Tuberculin skin test
Mantoux test

68

What is IGRA?

IFN-gamma test

69

What is done about latent infections?

What does this do?

Isoniazid for six months

Reduces re activation by up to 90%

70

How come a single drug is used in latent infection?

Because the numbers are so low

71

What vaccine do be have for TB?

What sort of vaccine is it?

BCG: Bacille Calmette Guerin

Live attenuated

72

Is BCG a good vaccine?

100% conversion to tuberculin positive

Variable immunity: 0-80%

73

Who do we give the vaccine to?
Who can't we give it to?

Give to:
- children
- people in endemic areas

Don't give it to:
- HIV / AIDS
- Immuno compromised

74

What happens is a granuloma can't form?

Overwhelming infection

Also infection with other mycobacteria

76

In what circumstances would a granuloma not form?

Depleted CD4+ (HIV)
TNF production inhibited

77

Describe the different ways droplet nuclei can be produced

Talking
Coughing
Sneezing

78

What is so bad about droplet nuclei?

• remain in air for ages
• small enough to avoid muco-ciliary elevator

79

Which is the most Th subtype in tuberculosis infection?

What are the most important cytokines that this type releases?

Th1

• TNF-a
• IFN-gamma

80

Which cytokines do infected alveolar macrophages release?

IL-1
IL-12
TNF-alpha

81

Which cytokine drives granuloma formation?

TNF-alpha

82

Are individuals with latent infection infectious?

No

83

Is primary TB common?

Not really
5% of cases of infection will result in primary TB

84

Are any of the RIPE drugs prodrugs?

Yes

85

Describe how resistance to treatment with RIPE occurs

Since some of the RIPE drugs are prodrugs, mutations can occur in the activating enzymes

Prodrug never activated