Tuberculosis and Leprosy Flashcards
What type of bacteria is the cause of tuberculosis and leprosy?
mycobacteria
M. tuberculosis
- causative agent of tuberculosis in humans
- often called TB (tubercle bacilli)
M.bovis
- causes tuberculosis in cows, rarely in humans
- humans can be infected by the consumption of unpasteurized milk leading to extrapulmonary TB
M. avium
- can cause tuberculosis-like illness in humans, particularly in AIDS patients
M. leprae
causative agent of leprosy in humans
What fraction of the world is affected with latent TB?
- 1/4 (carrier to the disease)
- 5-10% of these people with develop active TB in their lifetime
- greater rates in countries without access to medical care/treatment
How does TB spread?
through the air; if not treated, each person with active TB can infect 10-15 people a year
What is the leading killer among people living with HIV?
TB
The pathogen: Mycobacterium tuberculosis
- isolated by Robert Koch in 1882
- intracellular pathogen (lives inside macrophages)
- can be grown in the lab on specialized media but takes 4-6 weeks to get small colonies
- slow generation time of > 15hrs
Mycobacterium tuberculosis - what is the cell wall made of?
- have unusual cell envelope with high concentrations of mycolic acid - “waxy”
What is the cell wall of M.tuberculosis resistant to?
- many antibiotics
- killing by acidic and alkaline compounds
- osmotic lysis via complement deposition
- lethal oxidative stress promoting survival inside of macrophages
Why is the Acid Fast stain used for mycobacteria?
the waxy, lipid-rich cell envelope (very hydrophobic) resists common strains (Gram
Acid Fast Stain
- stained with carbol-fuchsin dye with slow heating (to melt the wax)
- washed with EtOH and HCl
- counter stained with methylene blue
- acid-fast organisms appear red whereas non-acid fast organisms appear blue
Acid-fastness is due to the presence of ____?
mycolic acid
Stage 1 of Tuberculosis
- transmission from inhalation of droplets from an infected host, usually by coughing or sneezing
- coughing/sneezing can generate 3000 droplet nuclei; droplet nuclei contain ~3 bacteria
- small diameter droplets can stay airborne for extended periods of time
T/F: Latent TB can still be transmitted.
FALSE - only active TB can be transmitted
Stage 2 of Tuberculosis
- begins 7-21 days after initial exposure
- phagocytosis of TB cells by lung (alveolar) macrophages
- TB inhibits the fusion of the lysosome to the phagosome and can multiply in macrophages
- macrophages will lyse and release TB cells to infect more macrophages
What is a key virulence property of M. Tuberculosis?
the ability to survive within the host macrophage
Stage 3 of Tuberculosis
- infected macrophages may form granulomas
- TB granulomas are “tubercles” of immune cells that try to destroy invading pathogens (typically formed by macrophages)
- the 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
Stage 4 of Tuberculosis
- some macrophages remain unactivated and infected
- the tubercle 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 centre can liquefy leading to cavitation
Pulmonary Tuberculosis
- 75%
- progressive, irreversible lung destruction can occur, and the bacteria may enter the bloodstream
- it is thought that a single inhaled bacterium can infect
Extra pulmonary tuberculosis
- more likely to occur in immunocompromised individuals
can infect: bone, joints, liver, spleen, gastrointestinal tract and brain - systemic spread, called miliary tuberculosis, is almost always fatal
What percent of TB infected people develop the active disease?
5-10%
What are the Symptoms of Tuberculosis
- often non specific
- a prolonged (> 2 weeks) cough with thick and possibly blood in mucus
- fever, chills, night sweats
- fatigue and weakness
- chest pain and shortness of breath
- loss of appetite and weight loss (“consumption”)
- pallor, meaning pastiness or pale skin (“the white death”)
- extra pulmonary depends on where TB has spread
Testing and Diagnosis of TB
- tuberculin test (PPD = purified protein derivative from M. tuberculosis)
- T cell mediated response
- positive test result is a red swollen circle at 48 hr
- a person is considered infected if the CONVERT from negative to positive on a TB sin test
What could a negative result in a TB test mean?
- not infected
- immune compromised (e.g. AIDs)
- not infected long enough
What could a positive result in a TB test mean?
- latent or active TB
- BCG vaccinated
- previously infected
What would happen if you got a positive TB skin test?
- careful history and 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
What are the hallmark of TB?
Lesions
Treatment of TB
- if untreated, active TB kills 2/3 of people
- six months of antibiotics for short treatment (slow growth means long treatments)
- multiple types of antibiotics are used
What does the antibiotic Rifampin do?
inhibits RNA polymerase
What does the antibiotic Isoniazid do?
inhibits mycolic acid synthesis
Why do you give two or more drugs for the treatment of TB?
if you have bacterial cells resistant to one, you have a backup to kill the others.
Multi-Drug Resistant TB
being resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampib
Extensively-Drug Resistant TB
- also resistant to the most effective SECOND-line drugs commonly used to treat MDR-TB
- found in all regions of the world
- strains have be virtually untreatable
Spectinamides
- chemically modified from spectinomycin
- narrow spectrum = high specificity for TB
- not pumped out of TB cells
- low toxicity for host cells
- works in mice
- presents antibiotic from being pumped out from bacteria
- inhibits the ribosomes but doesn’t get pumped out of transporter
“bacille Calmette-Guerin” (BCG)
- a living vaccine prepared from attenuated M. bovis
- BCG shares antigenicity with TB
- controversial due to variable efficacy (~80% or much less for pulmonary TB)
- effective against miliary TB
- vaccinated individuals get a false positive for the tuberculin test
- vaccination leaves large scars
- recommended for individuals with high risk to exposure
Tuberculosis and HIV/AIDS
- Individuals infected with HIV are ~25-times more likely to develop active tuberculosis
- One third of the persons living with HIV infection are co-infected with TB
- TB is a leading killer of HIV-positive people
~ 400,000 deaths per year are HIV/TB coinfections
What bacteria causes leprosy?
Mycobacterium leprae
what is another name for leprosy?
Hansen’s disease
What type of progression (slow/fast) does leprosy have?
slow - incubation period ~ 5years (if exposed to the bacteria, takes this long to develop the disease)
Where can leprosy cause damage?
permanent damage to skin, nerves, limbs, and eyes
T/F: Leprosy is very rare in developed countries
True
Approximately how many people are permanently disable by leprosy?
2 million
Describe M. leprae
- gram positive acid fast
- rod shaped
- waxy cell envelope (mycolic acid)
- cannot be cultivated in vitro (less well-studied than M.tuberculosis)
- can grow in food pads of mice (low numbers)
- causes systemic infection in the armadillo
What part of the body does M. leprae infect?
macrophages of skin and Schwann cells in nerves
Stigma around leprosy
- victims have been ostracized
- lesions of leprosy are visible whereas in tuberculosis they are hidden
- BUT, leprosy is much less infectious than TB
Is leprosy just as, less, or more infectious than TB?
less
What are the two major forms of leprosy?
Tuberculoid and Lepromatous
Tuberculoid Leprosy
- cell-mediated immunity present
- macrophage 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
- Tuberculoid Leprosy can be self-limiting
Lepromatous Leprosy
- cell-mediated immune responses are absent
- macrophages are not activated
- M. leprae survives and multiples in macrophages and Schwann cells
- Schwann cells provide myelin insulation to peripheral nerves
- due to nerve damage and loss of sensation leads to inadvertent traumatic lesions on the face and extremities
- can cause loss of eyebrows, thickening and enlarged nares, ears and cheeks “lion like” appearance
- lesions can become secondarily infected, eventually resulting in bone resorption, disfigurements and mutilation
Spread and Progression of Leprosy
- transmission is not well understood
- probably close (direct) contact for extended periods of time - inhaled droplets?
- most exposed individuals do not develop disease – host genetics likely plays an important role
Treatment of Leprosy
- highly treatable with antibiotics
- multiple drugs are used (6 months to 1 year)
- patients no longer transmit the disease after one dose of MDT
What drugs consist of MDT and when was it introduced?
1980s
- dapsone, rifampin, clofazimine
What drug was used to treat leprosy in the 1940s and why was it stopped?
dapsone, but resistance developed in the 1960s
