Tuberculosis Summary Flashcards
M.prototuberculosis evolved into?
7 different lineages
Lineage 2 is associated with which region?
East Asia
Lineage 3 is associated with which regions?
India and East Africa
Lineage 4 is associated with which region?
Europe
Lineages 5 and 6 are associated with which regions?
West Africa
Mycolic acid length?
C60-C90
What is mycolic acid?
Beta-hydroxy fatty acid with alpha alkyl side chain
Ketomycolates fold into which conformation?
W conformation
Describe the W conformation?
4 chains in parallel
What are the 4 types of receptors on macrophages?
Scavenger receptors
Opsonising receptors (FcR and complement receptors)
Innate immune sensors (TLR)
C-type lectin (mannose binding lectin, DC-Sign, dectin-1, dectin-2)
What are some examples of opsonins?
Surfactants SP-A and SP-D
IgG
Complement proteins e.g. C3b
Complement receptor 3 Mtb complex results in?
Phagosome arrest
Prevents respiratory burst
TLR2 recognises?
19kDa LP
Lipomannan LM
Lipoarabinomannan LAM
Granuloma formation is aided by which cytokines?
IL-12
IFN-g
TNF-alpha
Granuloma formation is suppressed by which cytokine?
IL-10
How can Mtb prevent destruction in macrophages?
Phagosomal maturation arrest
Prevention of phagolysosome formation
Ways that Mtb can prevent destruction in macrophages?
Receptors involved in Mtb uptake
Altering the phagosomal lumen
Altering in the phagosomal membrane
Receptors involved in Mtb uptake?
CR3-Mtb complex prevents respiratory burst and leads to phagosome maturation arrest
Altering the phagosomal lumen?
SapM
PknG
Urease C
LAM
What is SapM?
Secretory phosphatase
How does SapM work?
Need phosphatidylinositol-3-phosphate (PI3P) on the surface in order to allow phagolysosome fusion. SapM dephosphorylates PI3P and leads to phagosome maturation arrest.
What is PknG?
It is a secretory kinase
Serine/threonine kinase
How does PknG work?
It is a secretory kinase
It prevents phagosome-lysosome fusion
How does LAM work?
Prevents the increase of intracellular Ca2+ which prevents phagosome maturation
Urease C?
It leads to the production of ammonia which can neutralise the acidic phagosome
Alteration of the phagosomal membrane?
V-ATPase
Able to prevent acidification of the phagosome
Phagosomal arrest does not occur in?
Activated macrophages
What activates macrophages?
Opsonins binding opsonin receptors
IFN-gamma
TNF-alpha
Phagosome is acidified to what pH?
~4.5
What are γδ T cells?
They are non-classical T cells and are involved in recognising lipid antigens
γδ T cells can recognise antigens without?
Without the need for antigen to be presented on MHC
What are CD1 restricted T cells?
Recognise lipid antigen e.g. LAM, mycolic acid antigens presented on CD1 molecules.
Non-classical presentation of antigen on CD1
What are non-oxidative mechanisms of macrophage microbicidal activity?
Autophagy- Immunophagy
Apoptosis
The immunological induction of autophagy is known as ?
Immunophagy
Autophagy process?
Formation of an autophagosome
The autophagosome is a double membrane- can surround the Mtb and fuse with the lysosome for degradation
When is autophagy activated in cells?
In times of stress/ starvation
What is autophagy used for in cells that are not infected?
In times of starvation, organelles that are not being used/ proteins can be degraded and recycled to provide nutrients using autophagy
Describe the antibiotic treatment and length of treatment for DOTS?
Directly observed treatment- short course
6 months
2 months: Rifampin, pyrazinamide, isoniazid and ethambutol
4 months: Rifampin and isoniazid
Describe the antibiotic treatment and length of treatment for DOTS-Plus
24 months+
Use of second line drugs such as fluoroquinolone
What is MDR TB?
Resistant to rifampin and isoniazid
What is XDR TB?
Extensively drug resistant
Resistant to rifampin and isoniazid
Also resistant to fluoroquinolone and another second line antibiotic
Which antibiotics are prodrugs?
Pyrazinamide and isoniazid
Which antibiotics are cell wall synthesis inhibitors?
Ethambutol and isoniazid
Which drug has great penetrative capabilities?
Pyrazinamide
Which drug has poor penetrative capabilities?
Clofazimine
What is the new TB antibiotic drug?
Bedaquiline
Bedaquiline action?
Inhibits ATP synthase
Action of rifampin?
Inhibits DNA dependent RNA polymerase
Prevents transcription
Resistance to rifampin
Mutations in rpoB gene
Action of isoniazid?
Cell wall synthesis inhibitor
Prevents mycolic acid synthesis mainly through inhibition of InhA
Isoniazid prodrug activation?
Via catalase peroxidase encoded by katG
Isoniazid resistance?
Mutations in katG and inhA genes
Pyrazinamide action?
Energy inhibitor
Disrupts membrane potential
In acid pH uncharged protonated pyrazinoic acid and protons cross the membrane and disrupt membrane potential
Pyrazinamide prodrug activation?
Pyrazinamidase enzyme
Pyrazinamidase enzyme is encoded by?
pncA
Resistance to pyrazinamide?
Mutations in pncA
Ethambutol action?
Cell wall synthesis inhibitor
Prevents arabinogalactan synthesis
Inhibits arabinosyl transferases
Resistance to ethambutol?
Mutations in the gene encoding arabinosyl transferases
Streptomycin action?
Protein synthesis inhibitor
Binds to and blocks 30S subunit of the ribosome and associated 16S rRNA
Streptomycin resistance?
Mutationsin 16S rRNA
Fluoroquinolone action?
DNA replication inhibitor
Can inhibit action of DNA gyrase or topoisomerase IV
Quinolone antibiotic resistance?
Mutations in DNA gyrase
Pharmacodynamic considerations?
Impact of the drug on the organism
Ability of the antibiotic to clear infection and act on bacterial cells, especially those persisters
Pharmacokinetic considerations?
Impact of the organism on the drug
Ability of the drug to penetrate the granulomas
Why are the granulomas hard for antibiotics to penetrate?
Caseum where the bacteria are found has low vascularity
Why are some cells hard for antibiotics to impact?
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.
