Lecture 19 - Tuberculosis Flashcards
How long has tuberculosis been around?
When was it discovered?
Been around for centuries
Discovered in the 1880s
Which bacteria cause TB?
M. tuberculosis
M. bovis
What does infection usually present as?
Chronic pneumonia
Describe the onset of TB
Insidious
Slow, eventually getting worse and worse
What are the symptoms of TB?
- Cough
- Weight loss
- Fever
- Chills
Which organs are affected in TB?
Usually lungs
Other organs can be affected:
- lymph nodes
- brain
- bone
- urinary tract
Is TB an important disease?
2nd most common infection after HIV
Third of the world infected
8.8 million deaths in 2010
Compare ‘infection’ and ‘disease’
Latent infection: immune system is controlling disease
- no symptoms
Disease: bacteria escape the immune response
- symptoms
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
Which parts of the world experience the most TB infection?
Southern half of African continent
Russia
Asia
South east asia
How many species are there in the Mycobacterium genus?
Are they all pathogens?
There are many
Most are harmless
Some cause disease
What does M. tuberculosis cause?
What is the reservoir?
TB
Humans
What does T. bovis cause?
What is the reservoir?
TB
animals
What does M. ulcerans cause?
What is the reservoir?
Skin ulcers
Environment
What does M. leprae cause?
What is the reservoir?
Leprosy
Humans
What does MAC cause?
What is the reservoir?
TB-like disease in AIDS patients
Environmental
Are M. bovis infections commonly seen?
Not really anymore
Due to pasteurisation of milk
What are the oxygen requirements of M. tuberculosis?
Aerobic
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
Describe the structure of the cell wall of M. tb
Plasma membrane Peptidoglycan Arabinogalactam Mycolic acids Superficial lipids LAM: lipoarabinomannam
In one word, describe the cell wall of M. tb
Waxy
What can’t the gram stain be used to visualise M. tuberculosis?
The cell wall is resistant to other dyes
How is M. tuberculosis stained?
Ziehl-Nielsen
- Carbon fuschin (strong dye) added for 10 minutes
- Every thing is now pink
- Decolorise with acid-alcohol
- Only M. tuberculosis retain the pink dye
- Everything else counter stained with a blue dye
How does M. tuberculosis get into us?
- Infected person has open lung lesion
- Infected person coughs / sneezes / talks
- Droplet nuclei released into air and remain for hours
- Droplet nuclei inhaled
Once inhaled, what happens to M. tuberculosis in terms of immune response?
Avoids mucociliary elevator
Taken up by alveolar macropahages
Describe the normal innate response when microbes penetrate into the lower respiratory tract (LRT)
- Microbe binds to PRR / antibody / C’
- Phagocytosis by alveolar macrophage
- Phagolysosome formation
- Degradation
- Presentation of antigen on MHC II
- Release of cytokines
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
Normally, how are microbes broken down in the phagolysosome?
- Hydrolytic enzymes
- Reactive oxygen species (ROS)
- Reactive nitrogen species (NO)
Describe the innate responses in the LTR when droplet nuclei penetrate
- M. tuberculosis binds to PRR
- Phagocytosis
3a. Bacterium prevents lysosome fusion with the endosome
3b. Produces ammonium to keep the pH in the phagosome high - Survival and replication of the bacterium
- Some degradation –> MHC II presentation
- Cytokines release
What prevents lysosome fusion with the phagosome?
Mycobacterial lipids
Which cytokines are released by alveolar macrophages when M. tuberculosis is taken up?
IL-1
IL-8
IL-12
TNF-a
What do infected / activated macrophages then do?
- Migrate to local / hilar lymph node
- Activate Th cells
- Skewed response to Th1
Which cytokine released by the APC skews Th cells to Th1?
IL-12
What does Th1 produce?
IFN-gamma
Which T helper cells are induced?
Th1
Th17 to a lesser degree
What is the role of Th17?
Neutrophil activation
What do the activated CD8+s do?
Return to site of infection
What do the cytokines released by Th1 bring about?
TNF-a
IFN-g
- Inflammation
- Tissue damage
- Macrophage activation
What symptoms does IL-1 bring about?
Fever
What does TNF-a bring about?
Weight loss
Granuloma formation
Death of some infected MFs
Which cells go on to form a granuloma?
Monocytes
T lymphocytes
Neutrophils
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
- Macrophages release IL-8, IL-1, TNF-a
- • IL-8: neutrophil recruitment
• IL-1: fever
• TNF-alpha: granuloma formation, weight loss
What is the structure of a granuloma?
Multinucleate giant cell
Epithelioid cells
T Lymphocytes
What is a tubercle?
Another word for a granuloma
How do multinucleate cells form?
Fusion of macrophages
What is the purpose of a granuloma?
Walls off the infection
Contains the infection in 90% of cases
When does latent infection occur?
90% cases
Immune response contains the infection (granuloma, DTH)
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
In which people do we see primary and secondary TB?
Elderly
Young
HIV / immuno compromised
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
- Caseous necrosis
- cavitation
- Enlargement of granulomas
- Increased immune response
- Tissue damage
What happens in the lung when the bacteria reactivate?
Tubercle formation
Caseous necrosis
Liquefaction
Cavitation
What causes the classical symptoms of TB?
Tissue damage
Cytokines: IL-1, TNF-alpha
Enlarged granulomas
Immune response
Describe the productive sputum
Contains large amounts of bacilli
Describe the Mantoux test
What conclusions can we make form the test?
- Inject tuberculin: purified TB antigen
- Active immune response: pre-formed memory T cells
- Induration
This test does not indicate immunity or disease, only infection
Which two tests look for infection, but can’t indicate immunity or disease?
Mantoux test
In vitro IFN-g test
Describe the in vitro test that is performed
What does this tell us?
What doesn’t it tell us?
- Collect blood sample
- Add to medium
- Add TB antigen
- Incubate
- Memory T cells will release IFN-g if present
- Test for IFN-g
Only tells us if there is infection; we can’t conclude that there is disease or immunity
What test can be performed to identify disease?
- Chest X ray
- acid fast staining of sputum
- culture on enriched medium
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
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
What does the R in RIPE stand for?
Rifampin
What does the I in RIPE stand for?
Isoniazid
What does the P in RIPE stand for?
Pyrazinamide
What does the E in RIPE stand for?
Ethambutol
How do isoniazid and pyrazinamide work?
Must be activated by mycobacterium before they are active
How can Mycobacterium gain resistance to Isoniazid and pyrazinamide?
Mutations in the enzymes that active the drugs
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
Which people should be screened for TB?
Children
Immuno compromised
People in contact
What is TST?
Tuberculin skin test
Mantoux test
What is IGRA?
IFN-gamma test
What is done about latent infections?
What does this do?
Isoniazid for six months
Reduces re activation by up to 90%
How come a single drug is used in latent infection?
Because the numbers are so low
What vaccine do be have for TB?
What sort of vaccine is it?
BCG: Bacille Calmette Guerin
Live attenuated
Is BCG a good vaccine?
100% conversion to tuberculin positive
Variable immunity: 0-80%
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
What happens is a granuloma can’t form?
Overwhelming infection
Also infection with other mycobacteria
In what circumstances would a granuloma not form?
Depleted CD4+ (HIV)
TNF production inhibited
Describe the different ways droplet nuclei can be produced
Talking
Coughing
Sneezing
What is so bad about droplet nuclei?
- remain in air for ages
* small enough to avoid muco-ciliary elevator
Which is the most Th subtype in tuberculosis infection?
What are the most important cytokines that this type releases?
Th1
- TNF-a
- IFN-gamma
Which cytokines do infected alveolar macrophages release?
IL-1
IL-12
TNF-alpha
Which cytokine drives granuloma formation?
TNF-alpha
Are individuals with latent infection infectious?
No
Is primary TB common?
Not really
5% of cases of infection will result in primary TB
Are any of the RIPE drugs prodrugs?
Yes
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
