Tuberculosis

Question 1

What is tuberculosis (TB)?

Answer 1

▪ Airborne infection
▪ Intracellular bacilli (macrophages)
▪ Primarily a pulmonary disease but also extra-pulmonary TB
▪ Granuloma formation
▪ Latent and active form of disease (90% latent)

Question 2

What is a granuloma when taking about tuberculosis?

Answer 2

A granuloma is a structure formed during inflammation that is found in many diseases
It is a collection of immune cells known as macrophages
Granulomas form when the immune system attempts to wall off substances it perceives as foreign but is unable to eliminate

Question 3

What is the % of tuberculosis-latent and active disease?

Answer 3

Tuberculosis-latent disease is 90%

Tuberculosis-active disease is 10% => formation of caseous granuloma (granuloma involving necrosis)

Question 4

What are the 3 disease groups caused by mycobacteria (mycobacteriosis)?

Answer 4

▪ Tuberculosis: aerosol route (affects lungs and when disseminated => all organs)
▪ Tuberculosis-like: environmental mycobacteria (affects lungs, lymph nodes and skin)
▪ Leprosy: close person-to-person contact (affects skin plaques => damaged nerves and subsequent sensory loss)

Question 5

Why is mycobacteria so resistant?

Answer 5

The thick cell wall of mycobacteria provides protection and resistance to:
• many antibiotics
• lethal oxidative stress and survival inside phagosome of macrophages

Question 6

What can be said about the epidemiology of tuberculosis?

Answer 6

▪ About 1/4 of the global population are estimated to be carriers of a latent M. tuberculosis infection (asymptomatic = not contagious)
▪ Among the top 10 causes of death, more than HIV

Question 7

What other co-infection plays an important role in tuberculosis incidence rate?

Answer 7

HIV! (typically Africa where HIV is high)

Question 8

Why is it important to identify persons with the latent form of tuberculosis?

Answer 8

Because if they belong to a risk group (HIV infected) they might develop it later, so it is possible to to preventive treatment

Question 9

What can be said on the transmission of tuberculosis?

Answer 9

▪ Transmission (similar to SARS-CoV-2):
→ Person-to-person: coughing, sneezing, singing etc.
→ Aerosol
→ Close contacts
→ Only individuals with active disease are contagious

Question 10

What factors are taken into consideration for tuberculosis transmission?

Answer 10

→ the infectiousness of the person with TB (the number of organisms expelled into the air)
→ the environment in which exposure occurred (closed or open/ventilated area)
→ the duration of exposure
→ the susceptibility of the host
→ the virulence of the bacteria

Question 11

Which organs can be affected by tuberculosis?

Answer 11

▪ Any organ can be affected:
→ Pulmonary TB
→ Extrapulmonary TB
→ Dissiminated TB

Question 12

What are the clinical symptoms of tuberculosis?

Answer 12

→ cough, chest pain, weakness, chills, fever, night sweats, weight loss
→ unspecific! (similar to Covid-19)

Question 13

When is the greatest risk to develop tuberculosis?

Answer 13

The risk of developing active TB is greatest the first years after Mtb exposure

Question 14

What are the risk factors for developing tuberculosis?

Answer 14

▪ Immune suppression/weakening:

• HIV co-infection
• diabetes co-morbidity
• malnutrition
• poverty, crowded living conditions
• immunosupressive treatment
• drug abuse
• age (children, elderly)
• smoking (more than 20 cigarettes a day)

Question 15

What are the challenges with diagnosis of tuberculosis?

Answer 15

Difficult, slow, unspecific, low sensitivity and high costing

Question 16

What is the only tuberculosis vaccine available?

Answer 16

BCG vaccine: live attenuated bovine TB => but it gives limited protection
All new vaccine candidates have failed so far

Question 17

How can tuberculosis be treated?

Answer 17

With antibiotics, combination therapy, using a cocktail of 3-4 drugs:

• First-line (primary) drugs
• Second-line (secondary) drugs

Question 18

How long does it take to treat tuberculosis?

Answer 18

▪ Treatment scheme:
- “Intensive phase” first 2 months: all 4 first line drugs
- “Continuation” phase, at least 4 months
- Side effects: liver damage
▪ 2 weeks after treatment starts patients are no longer infectious

Question 19

Why is it difficult to treat tuberculosis with drugs?

Answer 19

▪ Mtb is intrinsically resistant to many antibiotics
▪ Dormant bacteria inside granulomas have little metabolic activity to target and can serve as reservoir
▪ Environment of granuloma makes it difficult for drugs to reach bacteria
▪ Treatment with anti-TB drugs is long lasting and often associated with severe side-effects and multi-drug resistance

Question 20

How does the innate immune system react to mycobacterium tuberculosis (Mtb)?

Answer 20

▪ Mtb is an intracellular pathogen mainly infecting macrophages
▪ Innate immune receptor recognize mycobacteria
▪ Early response of inflammatory
▪ Macrophages cannot eliminate bacteria
▪ Immune evasion: inhibition of phagosome-lysosome fusion
▪ Apoptosis/necrosis of infected cells
▪ Take up of antigen/bacteria by phagocytic cells (macrophages, DCs, neutrophils)
▪ Triggering of adaptive immunity

Question 21

How does the adaptive immunity system activate during tuberculosis?

Answer 21

▪ Induction of a CD4+ Th1 immune response (via dendritic cell antigen presentation) characterized mainly by IFN∂ secretion which activates macrophages
▪ Additional help by induction of cytotoxic effector functions by CD8+

Question 22

What is a caseous granuloma when taking about tuberculosis?

Answer 22

Same as granuloma but with a necrotic core

Question 23

What are the stages of TB nascent granuloma formation?

Answer 23

1. Inhalation of bacteria
2. Alveolar macrophages take up bacteria and
   translocate into lung interstitium
3. Bacteria reproduce in macrophages, recruitment of innate immune cells (chemokines, cytokines)

Question 24

What are the stages of TB mature necrotic granuloma formation?

Answer 24

1. Dendritic cells transport bacilli/bacterial products to local lymph nodes to prime specific T-cells
2. Recruitment of monocytes and T-cells (Th1) to site of infection
3. T-cells form rim around macrophage core
4. Fibrotic encapsulation around granuloma

Question 25

What are the advantages and disadvantages of tuberculosis mouse models?

Answer 25

Advantages:

• same pathogen as human (mycobacterium tuberculosis)
• same infection route (lungs)
• similar immune response

Disadvantages:
-no latency
- different granuloma structure (no
necrosis)
- some immunological findings cannot be transferred