Tuberculosis Summary

Question 1

M.prototuberculosis evolved into?

Answer 1

7 different lineages

Question 2

Lineage 2 is associated with which region?

Answer 2

East Asia

Question 3

Lineage 3 is associated with which regions?

Answer 3

India and East Africa

Question 4

Lineage 4 is associated with which region?

Answer 4

Europe

Question 5

Lineages 5 and 6 are associated with which regions?

Answer 5

West Africa

Question 6

Mycolic acid length?

Answer 6

C60-C90

Question 7

What is mycolic acid?

Answer 7

Beta-hydroxy fatty acid with alpha alkyl side chain

Question 8

Ketomycolates fold into which conformation?

Answer 8

W conformation

Question 9

Describe the W conformation?

Answer 9

4 chains in parallel

Question 10

What are the 4 types of receptors on macrophages?

Answer 10

Scavenger receptors
Opsonising receptors (FcR and complement receptors)
Innate immune sensors (TLR)
C-type lectin (mannose binding lectin, DC-Sign, dectin-1, dectin-2)

Question 11

What are some examples of opsonins?

Answer 11

Surfactants SP-A and SP-D
IgG
Complement proteins e.g. C3b

Question 12

Complement receptor 3 Mtb complex results in?

Answer 12

Phagosome arrest

Prevents respiratory burst

Question 13

TLR2 recognises?

Answer 13

19kDa LP
Lipomannan LM
Lipoarabinomannan LAM

Question 14

Granuloma formation is aided by which cytokines?

Answer 14

IL-12
IFN-g
TNF-alpha

Question 15

Granuloma formation is suppressed by which cytokine?

Answer 15

IL-10

Question 16

How can Mtb prevent destruction in macrophages?

Answer 16

Phagosomal maturation arrest

Prevention of phagolysosome formation

Question 17

Ways that Mtb can prevent destruction in macrophages?

Answer 17

Receptors involved in Mtb uptake
Altering the phagosomal lumen
Altering in the phagosomal membrane

Question 18

Receptors involved in Mtb uptake?

Answer 18

CR3-Mtb complex prevents respiratory burst and leads to phagosome maturation arrest

Question 19

Altering the phagosomal lumen?

Answer 19

SapM
PknG
Urease C
LAM

Question 20

What is SapM?

Answer 20

Secretory phosphatase

Question 21

How does SapM work?

Answer 21

Need phosphatidylinositol-3-phosphate (PI3P) on the surface in order to allow phagolysosome fusion. SapM dephosphorylates PI3P and leads to phagosome maturation arrest.

Question 22

What is PknG?

Answer 22

It is a secretory kinase

Serine/threonine kinase

Question 23

How does PknG work?

Answer 23

It is a secretory kinase

It prevents phagosome-lysosome fusion

Question 24

How does LAM work?

Answer 24

Prevents the increase of intracellular Ca2+ which prevents phagosome maturation

Question 25

Urease C?

Answer 25

It leads to the production of ammonia which can neutralise the acidic phagosome

Question 26

Alteration of the phagosomal membrane?

Answer 26

V-ATPase | Able to prevent acidification of the phagosome

Question 27

Phagosomal arrest does not occur in?

Answer 27

Activated macrophages

Question 28

What activates macrophages?

Answer 28

Opsonins binding opsonin receptors IFN-gamma TNF-alpha

Question 29

Phagosome is acidified to what pH?

Answer 29

~4.5

Question 30

What are γδ T cells?

Answer 30

They are non-classical T cells and are involved in recognising lipid antigens

Question 31

γδ T cells can recognise antigens without?

Answer 31

Without the need for antigen to be presented on MHC

Question 32

What are CD1 restricted T cells?

Answer 32

Recognise lipid antigen e.g. LAM, mycolic acid antigens presented on CD1 molecules. Non-classical presentation of antigen on CD1

Question 33

What are non-oxidative mechanisms of macrophage microbicidal activity?

Answer 33

Autophagy- Immunophagy | Apoptosis

Question 34

The immunological induction of autophagy is known as ?

Answer 34

Immunophagy

Question 35

Autophagy process?

Answer 35

Formation of an autophagosome | The autophagosome is a double membrane- can surround the Mtb and fuse with the lysosome for degradation

Question 36

When is autophagy activated in cells?

Answer 36

In times of stress/ starvation

Question 37

What is autophagy used for in cells that are not infected?

Answer 37

In times of starvation, organelles that are not being used/ proteins can be degraded and recycled to provide nutrients using autophagy

Question 38

Describe the antibiotic treatment and length of treatment for DOTS?

Answer 38

Directly observed treatment- short course 6 months 2 months: Rifampin, pyrazinamide, isoniazid and ethambutol 4 months: Rifampin and isoniazid

Question 39

Describe the antibiotic treatment and length of treatment for DOTS-Plus

Answer 39

24 months+ | Use of second line drugs such as fluoroquinolone

Question 40

What is MDR TB?

Answer 40

Resistant to rifampin and isoniazid

Question 41

What is XDR TB?

Answer 41

Extensively drug resistant Resistant to rifampin and isoniazid Also resistant to fluoroquinolone and another second line antibiotic

Question 42

Which antibiotics are prodrugs?

Answer 42

Pyrazinamide and isoniazid

Question 43

Which antibiotics are cell wall synthesis inhibitors?

Answer 43

Ethambutol and isoniazid

Question 44

Which drug has great penetrative capabilities?

Answer 44

Pyrazinamide

Question 45

Which drug has poor penetrative capabilities?

Answer 45

Clofazimine

Question 46

What is the new TB antibiotic drug?

Answer 46

Bedaquiline

Question 47

Bedaquiline action?

Answer 47

Inhibits ATP synthase

Question 48

Action of rifampin?

Answer 48

Inhibits DNA dependent RNA polymerase | Prevents transcription

Question 49

Resistance to rifampin

Answer 49

Mutations in rpoB gene

Question 50

Action of isoniazid?

Answer 50

Cell wall synthesis inhibitor | Prevents mycolic acid synthesis mainly through inhibition of InhA

Question 51

Isoniazid prodrug activation?

Answer 51

Via catalase peroxidase encoded by katG

Question 52

Isoniazid resistance?

Answer 52

Mutations in katG and inhA genes

Question 53

Pyrazinamide action?

Answer 53

Energy inhibitor Disrupts membrane potential In acid pH uncharged protonated pyrazinoic acid and protons cross the membrane and disrupt membrane potential

Question 54

Pyrazinamide prodrug activation?

Answer 54

Pyrazinamidase enzyme

Question 55

Pyrazinamidase enzyme is encoded by?

Answer 55

pncA

Question 56

Resistance to pyrazinamide?

Answer 56

Mutations in pncA

Question 57

Ethambutol action?

Answer 57

Cell wall synthesis inhibitor Prevents arabinogalactan synthesis Inhibits arabinosyl transferases

Question 58

Resistance to ethambutol?

Answer 58

Mutations in the gene encoding arabinosyl transferases

Question 59

Streptomycin action?

Answer 59

Protein synthesis inhibitor | Binds to and blocks 30S subunit of the ribosome and associated 16S rRNA

Question 60

Streptomycin resistance?

Answer 60

Mutationsin 16S rRNA

Question 61

Fluoroquinolone action?

Answer 61

DNA replication inhibitor | Can inhibit action of DNA gyrase or topoisomerase IV

Question 62

Quinolone antibiotic resistance?

Answer 62

Mutations in DNA gyrase

Question 63

Pharmacodynamic considerations?

Answer 63

Impact of the drug on the organism | Ability of the antibiotic to clear infection and act on bacterial cells, especially those persisters

Question 64

Pharmacokinetic considerations?

Answer 64

Impact of the organism on the drug | Ability of the drug to penetrate the granulomas

Question 65

Why are the granulomas hard for antibiotics to penetrate?

Answer 65

Caseum where the bacteria are found has low vascularity

Question 66

Why are some cells hard for antibiotics to impact?

Answer 66

As these cells may be persisters. Many drugs only work effectively on active bacteria. Some bacilli in the granuloma are in a dormant state with low proliferative ability and low metabolic activity.