Tuberculosis and Leprosy

Question 1

What is M. bovis?

Answer 1

• causes tuberculosis in cows, rarely in humans

- humans can be infected by the consumption of unpasteurized milk leading to extrapulmonary tuberculosis

Question 2

What is M. avium?

Answer 2

• can cause a tuberclosis-like illness in humans, particularly in AIDS patients

Question 3

What is M. leprae?

Answer 3

• the causative agent of leprosy in humans

Question 4

What is Tuberculosis?

Answer 4

• infection by M. tuberculosis
• can be latent or active
• many people have the latent form
• contagious and spread through the air by people with active TB

Question 5

What is M. turberculosis?

Answer 5

• intracellular pathogen (lives within macrophages)
• can be grown in the lab on specialized media but takes 4-6 weeks to get small colonies
• slow generation time

Question 6

Mycobacteria structure

Answer 6

• have an unusual cell envelop with high concentrations of mycolic acid which is ‘waxy’
• the unusual cell envelope is associated with resistance to
• many antibiotics
• killing by acidic and alkaline compounds
• osmotic lysis via complement deposition
• lethal oxidative stress promoting survival inside of macrophages
• impermeability to stains and dyes
• gram-positive acid-fast stain
• waxy lipid-rich cell envelope resists common strains

Question 7

What are acid-fast stain

Answer 7

• stained with carbol-fuchsin dye with slow heating (to melt wax)
• washed with EtOH and HCl
• counterstained with methylene blue
• acid-fast organisms appear red whereas non-acid fast organisms appear blue

Question 8

What is stage 1 of the spread and progression of tuberculosis?

Answer 8

• transmission is from inhalation of droplets from an infected host, usually by coughing or sneezing
• coughing/sneezing can generate 3000 droplet nuclei
• droplet nuclei can contain around 3 bacteria
• small diameter droplets can stay airborne for extended periods of time
• airborne droplets can be inhaled directly into the lungs

Question 9

What is stage 2 of the spread and progression of tuberculosis?

Answer 9

• phagocytosis of TB cells by lung (alveolar) macrophages
• TB blocks acidification of the phagosome
• inhibits the fusion of the lysosome to the phagosome
• multiplies in macrophages
• macrophages lyse and release TB cells to infect more macrophages

Question 10

What is stage 3 of the spread and progression of tuberculosis?

Answer 10

• infected macrophages may form granulomas
• TB granulomas are “tubercles” of immune cells that try to destroy invading pathogens (typically formed by macrophages)
• granuloma represents a “balance” between the pathogen and the host -> latent infection
• T cell activated macrophages can kill TB
• activated T cells can secrete cytokines (IFN-gamma) to activate the macrophages
• macrophages at the center of the granuloma remain harder to activate by T cells
• chronic inflammation cause “cheese-like” necrosis
• caseous necrosis

Question 11

What is stage 4 of the spread and progression of tuberculosis?

Answer 11

• some macrophages remain unactivated and infected
• tubercule grows
• erosion of the granuloma into the airway provides the route of transmission
• deterioration of host immunity can result in a life-threatening infection
• active tuberculosis
• the caseous center can liquefy leading to cavitation

Question 12

What is extrapulmonary tuberculosis

Answer 12

• infection outside the lungs
• more likely to occur in immunocompromised (HIV-infected patients) individuals and young children
• can infect bone, joints, liver, spleen, gastrointestinal tract and brain
• widespread dissemination, called miliary tuberculosis is almost always fatal

Question 13

Testing and diagnosis

Answer 13

• tuberculin test (PPD = purified protein derivative from M. tuberculosis)
• based on T cell-mediated response

Question 14

Positive tuberculin test

Answer 14

• red and swollen circle at 48h
• a person is considered infected if they convert from negative to positive on a TB skin test
• latent or active TB
• BCG vaccinated
• previously infected
• a careful history and a chest X-ray
• X-ray: typical upper lobe “shadowing” -> lesions
• calcified granulomas may be seen on an X-ray
• staining of sputum for acid-fast bacilli and culturing

Question 15

Negative tuberculin test

Answer 15

• not infected
• immune-compromised (AIDS)
• not infected long enough

Question 16

Treatment

Answer 16

• active TB will kill 2 out of 3 people if untreated
• 6 months of antibiotics for the short treatment
• slow growth means long treatments
• generally, multiple types of antibiotics are used

Question 17

What are the multiple types of antibiotics are used?

Answer 17

• Rifampin (inhibits RNA polymerase)
• Isoniazid (inhibits mycolic acid synthesis)
• others…

Question 18

Drug-resistant TB

Answer 18

• multi-drug resistant TB (MDR-TB)
• defined as being resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampin
• XDR-TB has been found in all regions of the world
• these strains can be virtually untreatable

Question 19

Bacille Calmette-Guerin (BCG)

Answer 19

• a living vaccine prepared from attenuated M. Bovis
• shares antigenicity with TB
• controversial due to variable efficacy (80% or much less) for pulmonary TB
• effective against miliary TB
• vaccinated individuals can give a false positive for the tuberculin test
• vaccination leaves large scars
• recommended for individuals with high risk to exposure

Question 20

What is leprosy

Answer 20

• a chronic disease
• also called Hansen’s disease
• very slow progression
• the incubation period of around 5 years
• can cause permanent damage to skin, nerves, limbs and eyes
• leprosy is rare in developed countries
• shares some features with M. tuberculosis
• many people are disabled by leprosy, mainly in tropical developing countries
• Gram-positive, acid-fast, rod-shaped, waxy cell envelope (mycolic acid)
• cannot be cultivated in vitro
• can grow in footpads in armadillos
• infects macrophages of skin and Schwann cells in nerves

Question 21

History and leprosy

Answer 21

• victims have been ostracized
• rejected by families and friends
• driven from communities
• killed
• lesions in tuberculosis is “hidden”
• lesions in leprosy are “visible”
• but is much less infectious than TB

Question 22

What are the two forms of leprosy

Answer 22

• tuberculoid

- lepromatous

Question 23

What is tuberculoid leprosy?

Answer 23

• cell-mediated immunity present
• macrophages can contain the bacteria
• light coloured lesions with “anesthetic” areas
• sometimes loss of hair and pigmentation
• patients become tuberculin positive (active T cell-mediated responses)
• bacterial cells are generally not recoverable from lesions
• can be self-limiting

Question 24

What is lepromatous leprosy?

Answer 24

• cell-mediated immune responses are absent
• macrophages are not activated
• M. leprae survives and multiplies in macrophages and Schwann cells
• due to nerve damage and loss of sensation leads to inadvertent traumatic lesion on the face and extremities
• can cause loss of eyebrows, thickening and enlarged noses, ears and cheeks
• lion-like appearance
• lesions can become secondarily infected, eventually resulting in bone resorption, disfigurements and mutilation

Question 25

Spread and progression of leprosy

Answer 25

• transmission is not well understood
• probably close (direct) contact for extended periods of time
• inhaled droplets?
• most exposed individuals do not develop the disease
• host genetics likely plays an important role

Question 26

Treatment of leprosy

Answer 26

• treatable with antibiotics
• multiple drugs are used (6 months to a year)
• clapsone - resistance developed in the 1960s
• multidrug therapy (MDT) - dapsone, rifampin, clofazimine
• patients no longer transmit the disease after one dose of MDT