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MIIM20002 - Microbes, Infections, Responses > Lecture 19 - Tuberculosis > Flashcards

Lecture 19 - Tuberculosis Flashcards

0
Q

How long has tuberculosis been around?

When was it discovered?

A

Been around for centuries

Discovered in the 1880s

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1
Q

Which bacteria cause TB?

A

M. tuberculosis

M. bovis

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2
Q

What does infection usually present as?

A

Chronic pneumonia

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3
Q

Describe the onset of TB

A

Insidious

Slow, eventually getting worse and worse

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4
Q

What are the symptoms of TB?

A
  • Cough
  • Weight loss
  • Fever
  • Chills
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5
Q

Which organs are affected in TB?

A

Usually lungs

Other organs can be affected:

  • lymph nodes
  • brain
  • bone
  • urinary tract
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6
Q

Is TB an important disease?

A

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

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7
Q

Compare ‘infection’ and ‘disease’

A

Latent infection: immune system is controlling disease
- no symptoms

Disease: bacteria escape the immune response
- symptoms

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8
Q

Can TB causing bacteria be drug resistant?

Talk to this

A

Yes

This year, there have been completely drug resistant strains reported

Resistance occurs through improper treatment with antibiotics

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9
Q

Which parts of the world experience the most TB infection?

A

Southern half of African continent
Russia
Asia
South east asia

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10
Q

How many species are there in the Mycobacterium genus?

Are they all pathogens?

A

There are many
Most are harmless
Some cause disease

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11
Q

What does M. tuberculosis cause?

What is the reservoir?

A

TB

Humans

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12
Q

What does T. bovis cause?

What is the reservoir?

A

TB

animals

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13
Q

What does M. ulcerans cause?

What is the reservoir?

A

Skin ulcers

Environment

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14
Q

What does M. leprae cause?

What is the reservoir?

A

Leprosy

Humans

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15
Q

What does MAC cause?

What is the reservoir?

A

TB-like disease in AIDS patients

Environmental

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16
Q

Are M. bovis infections commonly seen?

A

Not really anymore

Due to pasteurisation of milk

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17
Q

What are the oxygen requirements of M. tuberculosis?

A

Aerobic

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18
Q

What are some of the features of M. tuberculosis?

What are these features due to?

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

Due to the unusual cell wall composition

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19
Q

Describe the structure of the cell wall of M. tb

A 
Plasma membrane
Peptidoglycan
Arabinogalactam
Mycolic acids
Superficial lipids
LAM: lipoarabinomannam
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20
Q

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

A

Waxy

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21
Q

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

A

The cell wall is resistant to other dyes

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22
Q

How is M. tuberculosis stained?

A

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
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23
Q

How does M. tuberculosis get into us?

A
  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
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24
Q

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

A

Avoids mucociliary elevator

Taken up by alveolar macropahages

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25
Q

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

A
  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
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26
Q

What are the different types of droplets?

He long does each stay in the air?

A

Large droplets: not very long

Small droplets: longer

Droplet nuclei: hours; indefinitely

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27
Q

Normally, how are microbes broken down in the phagolysosome?

A
  1. Hydrolytic enzymes
  2. Reactive oxygen species (ROS)
  3. Reactive nitrogen species (NO)
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28
Q

Describe the innate responses in the LTR when droplet nuclei penetrate

A
  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
  3. Survival and replication of the bacterium
  4. Some degradation –> MHC II presentation
  5. Cytokines release
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29
Q

What prevents lysosome fusion with the phagosome?

A

Mycobacterial lipids

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30
Q

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

A

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

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31
Q

What do infected / activated macrophages then do?

A
  1. Migrate to local / hilar lymph node
  2. Activate Th cells
  3. Skewed response to Th1
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32
Q

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

A

IL-12

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33
Q

What does Th1 produce?

A

IFN-gamma

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34
Q

Which T helper cells are induced?

A

Th1

Th17 to a lesser degree

35
Q

What is the role of Th17?

A

Neutrophil activation

36
Q

What do the activated CD8+s do?

A

Return to site of infection

37
Q

What do the cytokines released by Th1 bring about?

A

TNF-a
IFN-g

  • Inflammation
  • Tissue damage
  • Macrophage activation
38
Q

What symptoms does IL-1 bring about?

A

Fever

39
Q

What does TNF-a bring about?

A

Weight loss
Granuloma formation
Death of some infected MFs

40
Q

Which cells go on to form a granuloma?

A

Monocytes
T lymphocytes
Neutrophils

41
Q

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?

A

Later:
1. Stimulated by Th1, IFN-gamma

  1. Macrophages release IL-8, IL-1, TNF-a
  2. • IL-8: neutrophil recruitment
    • IL-1: fever
    • TNF-alpha: granuloma formation, weight loss
42
Q

What is the structure of a granuloma?

A

Multinucleate giant cell
Epithelioid cells
T Lymphocytes

43
Q

What is a tubercle?

A

Another word for a granuloma

44
Q

How do multinucleate cells form?

A

Fusion of macrophages

45
Q

What is the purpose of a granuloma?

A

Walls off the infection

Contains the infection in 90% of cases

46
Q

When does latent infection occur?

A

90% cases

Immune response contains the infection (granuloma, DTH)

47
Q

What is primary TB?

A

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

Immune system cannot control the infection

Insidious Pneumonia

Dissemination to other organs

48
Q

In which people do we see primary and secondary TB?

A

Elderly
Young
HIV / immuno compromised

49
Q

What is secondary tuberculosis?

Describe what happens

A

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
Q

What happens in the lung when the bacteria reactivate?

A

Tubercle formation
Caseous necrosis
Liquefaction
Cavitation

51
Q

What causes the classical symptoms of TB?

A

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

52
Q

Describe the productive sputum

A

Contains large amounts of bacilli

54
Q

Describe the Mantoux test

What conclusions can we make form the test?

A
  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
Q

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

A

Mantoux test

In vitro IFN-g test

55
Q

Describe the in vitro test that is performed

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

A
  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
Q

What test can be performed to identify disease?

A
  • Chest X ray
  • acid fast staining of sputum
  • culture on enriched medium
57
Q

Is M. tuberculosis easy to culture?

A

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
Q

What therapy is given to those with active disease?

A

Sorter course treatment - 6 months

Four 2 months:
RIPE:
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol

For 4 months :
Rifampicin
Isoniazid

59
Q

What does the R in RIPE stand for?

A

Rifampin

60
Q

What does the I in RIPE stand for?

A

Isoniazid

61
Q

What does the P in RIPE stand for?

A

Pyrazinamide

62
Q

What does the E in RIPE stand for?

A

Ethambutol

63
Q

How do isoniazid and pyrazinamide work?

A

Must be activated by mycobacterium before they are active

64
Q

How can Mycobacterium gain resistance to Isoniazid and pyrazinamide?

A

Mutations in the enzymes that active the drugs

65
Q

What is directly observed treatment?

A

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
Q

Which people should be screened for TB?

A

Children
Immuno compromised
People in contact

67
Q

What is TST?

A

Tuberculin skin test

Mantoux test

68
Q

What is IGRA?

A

IFN-gamma test

69
Q

What is done about latent infections?

What does this do?

A

Isoniazid for six months

Reduces re activation by up to 90%

70
Q

How come a single drug is used in latent infection?

A

Because the numbers are so low

71
Q

What vaccine do be have for TB?

What sort of vaccine is it?

A

BCG: Bacille Calmette Guerin

Live attenuated

72
Q

Is BCG a good vaccine?

A

100% conversion to tuberculin positive

Variable immunity: 0-80%

73
Q

Who do we give the vaccine to?

Who can’t we give it to?

A

Give to:

  • children
  • people in endemic areas

Don’t give it to:

  • HIV / AIDS
  • Immuno compromised
74
Q

What happens is a granuloma can’t form?

A

Overwhelming infection

Also infection with other mycobacteria

76
Q

In what circumstances would a granuloma not form?

A

Depleted CD4+ (HIV)

TNF production inhibited

77
Q

Describe the different ways droplet nuclei can be produced

A

Talking
Coughing
Sneezing

78
Q

What is so bad about droplet nuclei?

A
  • remain in air for ages

* small enough to avoid muco-ciliary elevator

79
Q

Which is the most Th subtype in tuberculosis infection?

What are the most important cytokines that this type releases?

A

Th1

  • TNF-a
  • IFN-gamma
80
Q

Which cytokines do infected alveolar macrophages release?

A

IL-1
IL-12
TNF-alpha

81
Q

Which cytokine drives granuloma formation?

A

TNF-alpha

82
Q

Are individuals with latent infection infectious?

A

No

83
Q

Is primary TB common?

A

Not really

5% of cases of infection will result in primary TB

84
Q

Are any of the RIPE drugs prodrugs?

A

Yes

85
Q

Describe how resistance to treatment with RIPE occurs

A

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

Prodrug never activated

MIIM20002 - Microbes, Infections, Responses (32 decks)

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