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Tuberculosis Flashcards

(104 cards)

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1
Q

How many people fell ill with TB and how many people died from TB in 2015?

A
  1. 4 million people fell ill

1. 8 million died from TB

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2
Q

Over 95% of TB deaths occur where?

A

In low and middle income countries

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3
Q

TB infections are most common in which countries?

A 
India
South Africa
Nigeria
China
Pakistan
Indonesia
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4
Q

How many people are latently infected with TB?

A

~2 billion

1/3 of the world’s population

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5
Q

What mycobacteria cause tuberculosis?

A

MTBC: Mycobacterium tuberculosis complex

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6
Q

What mycobacterium causes leprosy?

A

Mycobacterium leprae

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7
Q

What mycobacterium causes Buruli ulcers?

A

Mycobacterium ulcerans

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8
Q

What bacteria make up the mycobacterium tuberculosis complex?

A 
MBTCA
M= microti
B= bovis
T= tuberculosis
c= canetti
a= africanum
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9
Q

Which mycobacterium led to the BCG vaccine?

A

Mycobacterium bovis

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10
Q

Prototuberculosis developed into?

A

Different lineages

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11
Q

How did the different linages of TB form?

A

Through regions of deletion

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12
Q

Where are different lineages found?

A

Different lineages are found in different parts of the world. They have a phylogeographic population structure with different lineages associated with different human populations

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13
Q

Which lineage is most common in Europe?

A

Lineage 4

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14
Q

Which lineages are most common in West Africa?

A

Lineages 5 and 6

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15
Q

Which lineage is most common in India/East Africa?

A

Lineage 3

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16
Q

Which lineage is most common in East Asia?

A

Lineage 2

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17
Q

Lineage 2 is most common in?

A

East Asia

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18
Q

Lineage 3 is most common in?

A

India/East Africa

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19
Q

Lineages 5 and 6 belong to which member of the MTBC complex?

A

Mycobacterium africanum

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20
Q

Which lineages form a monophyletic group?

A

2,3,4

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21
Q

Lineages 2,3,4 form a monophyletic group through which unique deletion?

A

tbD1

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22
Q

Which region of deletion produces lineages 5 and 6?

A

RDL9

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23
Q

What is the MTBC?

A

Mycobacterium tuberculosis complex

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24
Q

Nucleotide sequence similarity in MTBC?

A

99.9% similarity at nucleotide level. Have host tropism and phenotypic and pathogenic differences.

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25
When did TB arise as a human pathogen?
~70,000 years ago
26
What are some key features of mycobacteria?
- aerobic - microaerophilic - non-motile - bacilli - slow growing
27
TB doubling time?
24 hours
28
Mycobacterium staining procedure is known as the?
Acid fast staining | Ziehl-Neelsen
29
What is another name for the acid fast staining procedure?
Ziehl-Neelsen
30
Steps in the acid fast staining procedure?
Add carbol-fuchsin dye Decolorise with acid-alcohol or acid-acetone solutions Add methylene blue counter stain to stain any cells which are not acid fast
31
Why are mycobacterium called acid fast?
They maintain the red colouration from the carbol-fuchsin dye as they resist decoloration by acid-alcohol and acid-acetone solutions
32
Describe the cell envelope of gram negative bacteria?
``` Plasma membrane Periplasmic space Thin peptidoglycan layer Periplasmic space Outer membrane with lipopolysaccharide ```
33
Describe the cell envelope of gram positive bacteria?
Plasma membrane Thick peptidoglycan layer Teichoic acids
34
What can be used to stain gram positive cells?
Crystal violet
35
What can be used to stain gram negative cells?
Counter stain safranin
36
Describe the mycobacterium cell envelope structure?
Plasma membrane PIM= phosphatidylinositol mannosides Peptidoglycan then this is covalently linked to arabinogalactan Arabinogalactan is covalently linked to mycolic acid Inner leaflet of the outer membrane= mycolic acid Outer leaflet of the outer membrane= extractible lipids including PIM and LAM= lipoarabinomannan Capsule made of lipids, proteins and polysaccharides
37
What is mycolic acid?
Mycolic acid= beta hydroxy fatty acid with alpha-alykl side chain
38
What is mycolic acid?
A beta hydroxy fatty acid with an alpha-alkyl side chain
39
Mycolic acid length?
C60-C90
40
Mycolic acid can form different?
Conformations
41
Why does mycolic acid need to fold into different conformations?
Full length mycolic acid would be too large for the inner leaflet of the outer membrane
42
Which mycolic acid conformation decreases the permeability of the inner leaflet and how?
W conformation of keto-mycolates. Folds into four chains in parallel. The tight packing aids the formation of an impermeable barrier
43
Mycobacterium tuberculosis infectivity?
Very infectious | Only a single particle is needed for infection
44
Which cells first phagocytose the mycobacterium tuberculosis bacilli?
The resident alveolar macrophages
45
What are the four categories of receptors found on macrophages?
Scavenging receptors Opsonising receptors C-type lectin receptors Innate immune sensors
46
What are opsonising receptors?
Fc receptors or complement receptors
47
What are c-type lectin receptors?
Mannose binding lectin dectin-1 dectin-2 DC-SIGN
48
What does TLR2 recognise?
``` 19kDa lipoprotein (LP) LAM= Lipoarabinomannan LM= Lipomannan ```
49
TLR2 signals via which pathway?
Myd88
50
TLR2 leads to the production of what?
Causes macrophages to produce IL-12
51
One of the major receptors you need to know on macrophages for phagocytosis?
CR3 | Complement Receptor 3
52
Tuberculosis-complement receptor 3 complex causes what?
Prevents respiratory burst | Blocks phagosome maturation
53
What are neutrophil NETs made out of?
DNA, histones, nucleosomes
54
What does NET stand for?
Neutrophil Extracellular Traps
55
What are lymphatic endothelial cells?
They line lymphatic vessels | The bacteria can hide in the lymph node and cause disease when conditions are more favourable
56
Which cytokines aid granuloma formation?
Pro-inflammatory cytokines: TNF-alpha IL-12 IFN-gamma
57
Which cytokines prevent granuloma formation?
Anti-inflammatory cytokines | IL-10
58
Which CD4+ response is important for granuloma formation?
Th1 response
59
How is the Th1 response activated?
Th0-->Th1 | Stimulated by IL-12
60
Describe the granuloma structure?
Necrotic area in the centre known as the caseum You then have lots of innate immune cells including: dendritic cells, foamy macrophages, multinucleated giant cells, NK cells and neutrophils. These are surrounded by a ring of lymphocytes
61
What are the main lymphocytes?
Mainly CD4+, CD8+, CD1 and γ/δ T cells
62
What is the caseum?
Necrotic centre Has a 'cheese-like' appearance Dead macrophages are found here Rich in lipids
63
Macrophages can become?
They can fuse to from large multinucleated cells | They can differentiate to become foamy macrophages
64
Foamy macrophages are?
Lipid rich
65
Foamy macrophages have lost?
Their phagocytic and bactericidal activities
66
Where is mycobacterium tuberculosis found in the granuloma?
Extracellularly in the caseum | Intracellularly in foamy macrophages
67
Why is the bacteria found in the caseum and in foamy macrophages?
They are lipid rich
68
What are the conditions within the caseum like?
Reduced vasculature Low oxygen levels This is why it is good that mycobacterium tuberculosis is a microaerophile
69
Reduced oxygen and nutrient levels lead to?
A reduction in metabolic activity | Reduction in cell division/proliferation
70
What can cause the latent infection to then re-activate?
Immunosuppression HIV Ageing Malnutrition
71
What is the role of vitamin D?
Has been shown to boost the immune system
72
How can mycobacterium tuberculosis prevent destruction within non-activated macrophages?
Prevents phagosome maturation and phagosome fusion with the lysosome= prevents phagolysosome formation.
73
What are the three ways in which mycobacterium tuberculosis can prevent destruction in non-activated macrophages?
1) Receptors involved in Mtb uptake 2) Alteration of phagosomal lumen 3) Alteration of phagosomal membrane
74
Receptors involved in Mtb uptake to avoid destruction?
The CR3-Mtb complex is able to prevent respiratory burst and prevent the maturation of the phagosome
75
Alteration of the phagosomal lumen?
sapM PknG Urease C LAM
76
sapM?
Phagosomal fusion requires the presence of PI3P on the surface of phagosomes PI3P= phosphatidylinositol-3-phosphate sapM is a secretory phosphatase which can dephosphorylate PI3P which arrests phagosome maturation
77
What is sapM?
A secretory phosphatase
78
What is PknG?
A secretory kinase | Serine/threonine kinase
79
What does PknG do?
Blocks phago-lysosome fusion
80
How does LAM prevent degradation in non-activated macrophages?
Inhibits cellular increase in Ca2+ | Phagosome maturation arrest
81
How does Urease C prevent phagolysosomal maturation?
Urease C drives neutralisation of acidification in phagosomes by generation of ammonia, thereby inhibiting phagolysosomal maturation
82
Modification of the phagosomal membrane?
Prevention of V-ATPase | By inhibiting its function acidification of the endosome is prevented
83
What is PknG?
A secretory serine/threonine kinase Able to prevent phagolysosome formation Phagosome and lysosome fusion is prevented
84
What is sapM?
It is a secretory phosphatase Dephosphorylates PI3P= phosphatidylinositol-3-phosphate which is required on the surface of phagosomes. Leads to the arrest of phagosomal maturation
85
Phagosomal arrest does not occur in?
Activated macrophages
86
How can macrophages overcome phagosomal arrest?
Through activation
87
How are macrophages activated?
Recognition of opsonised molecules | IFN-gamma production
88
What pH is the phagosome acidified to?
~4.5
89
How can the innate immune response promote the adaptive immune response? Provide an example?
Macrophages produce IL-12. This can then stimulate Th0-->Th1 which leads to the production of IFN-gamma which can then activate macrophages
90
What cells predominantly produce IFN-gamma?
CD4+ cells
91
CD8+ cells produce what to induce apoptosis/cell death?
Granulysin | Perforin
92
γδ T cells recognise antigens without?
Without the need for presentation on a major histocompatibility complex
93
γδ T cells recognise what type of antigens?
Lipid antigens
94
CD1 restricted T cells recognise?
Recognise lipid antigens abundant in the mycobacterial cell walls (LAM, PIM, mycolic acids) presented by the CD1 molecules
95
The T cells have which main two functions?
1. Direct cytotoxic activity | 2. Activation of the macrophages
96
Activated macrophage killing pathways?
Reactive oxygen and reactive nitrogen species
97
Reactive oxygen pathway?
Requires oxygen to make reactive oxygen species including superoxide and hydrogen peroxide
98
Reactive nitrogen pathway?
Requires L-arginine as a precursor to make e.g. nitric oxide and nitrogen dioxide
99
How do macrophages kill Mtb?
Oxidative and non-oxidative mechanisms
100
Non-oxidative mechanisms?
Autophagy- immunophage | Apoptosis
101
Autophagy stimulated by the immune system is known as?
Immunophagy
102
How can TB resist death in activated macrophages, what is a mechanism?
KatG
103
What is KatG?
Catalase peroxidase
104
What can KatG do?
Can inactivate reactive oxygen species within phagolysosomes

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