(B) Lecture 14: Tuberculosis and Leprosy Flashcards
Mycobacteria
- M. tuberculosis
- M. leprae
- M. bovis
- M. avium
M. tuberculosis is the agent for…
- causative agent of Tuberculosis in humans
- often called TB for tubercle bacilli
M. leprae is the agent for…
causative agent of Leprosy in humans
M. bovis is the agent for…
- causes tuberculosis in cows, rarely in humans
- humans can be infected by consumption of unpasteurized milk leading to extrapulmonary TB
M. avium
can cause TB-like illness in humans, especially in patients w/ AIDS
- usually in immunocompromised patients
Tuberculosis
- infection by M. tuberculosis
- can be latent (not transmissible) or active (transmissible)
- approx. 2 billion ppl (1/4 of world’s population) likely have latent TB
- TB is contagious + spreads through air by ppl w/ ACTIVE TB
- about 10% of ppl infected w/ latent TB develop active TB in their lifetime
Order of mortality of pathogens
- COVID
- TB
- HIV/AIDS
- Malaria
Mycobacterium tuberculosis
- INTRACELLULAR pathogen (lives within macrophages)
- SLOW generation time
- M. tuberculosis can be grown in the lab on specialized media
M. tuberculosis cell envelope
- have an unusual cell envelope w/ high conc of mycolic acid = WAXY
- impermeable to stains and dyes (gram POSITIVE ACID FAST STAIN) - hallmark
- lipid rich/waxy envelope is very hydrophobic and resists common stains
- mycolic acid causes “acid-fastness”
Unusual cell envelope is associated w/ resistance to:
- some antibiotics
- osmotic lysis via complement deposition
- lethal oxidative stress = survival inside of macrophages
Acid fast stain
- stained w/ carbol-fuschin dye w/ slow heating to melt wax
- washed w/ ethanol and HCl
- counter stained w/ methylene blue
- acid-fast organisms (like TB) appear red while non-acid fast organisms appear blue
Spread of TB
Stage 1
- transmission thru inhalation of droplets from infected host (coughing/sneezing)
- small droplets can stay airborne for extended periods of time
Spread and Progression of TB
Stage 2
- lung macrophages phagocytose TB cells
- TB blocks acidification of phagosome
- TB inhibits fusion of lysosome to phagosome
- TB multiplies in macrophages
- macrophages lyse + release TB cells to infect more macrophages
- TB delays dendritic cell migration to lymph nodes
ESX secretion systems
- 5 ESX systems exist in M. TB
- enables transport of select bacterial molecules across thick Mtb cell envelope
- multiple functions like damage to phagosome membrane
- also inhibits immune responses
Spread and progression of TB
Stage 3
- infected macrophages form GRANULOMAS
- TB granulomas are TUBERCLES of immune cells that try to destroy invading pathogens
granuloma represents a balance btwn pathogen and host = LATETNT INFECTION
- T-cell activated macrophage can kill TB
- activated T cells secrete cytokines (IFN-gamma) to activate macrophage
- macrophages at centre of granuloma are harder to activate by T cells
- chronic inflammation causes cheese-like necrosis = CASEOUS NECROSIS
Spread and progression of TB
Stage 4
- some macrophages remain unactivated and infected
- tubercle grows
- granuloma erodes into airway = route of transmission
- deterioration of host immunity = active TB
- caseous centre/lesions can liquefy and cause CAVITATION
Extrapulmonary TB
- infection OUTSIDE the lungs
- can infect multiple organ systems
- more likely to occur in immunocompromised
MILIARY TB (tiny lesions) = widespread dissemination (almost always fatal)
Testing and Diagnosis of TB
- Tuberculin test is injected under skin
- T cell-mediated response (2 days after)
- positive result= red and swollen at 48h
- infected if they convert from negative to positive on TB skin test
- a positive tuberculin test would mean a careful history and a chest X-ray
- X-ray: typical upper lobe shadow = lesions
- calcified granulomas may be seen on X-ray
- staining of sputum for acid fast
- IFN-gamma response assay (look at T cell specific response)
TB Test results
Positive test = red and swollen at 48h
Positive result could mean
- latent or active TB, BCG vaccinated, previously infected
Negative test could mean
- not infected, immune compromised, not infected long enough
Treatment of TB
- active TB can kill 2 of 3 ppl if untreated
- 6 months of antibiotics for short treatment
- slow growth = long treatments
Multiple types of antibiotics used
- Rifampin
- Isoniazid
Drug Resistant TB
Multi-drug resistant TB (MDR-TB)
- being resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampin
Extensively-drug resistant (XDR-TB)
- resistant to the most effective second-line therapeutic drugs used to treat MDR-TB
BUT new drugs are being developed.
Rifampin
antibiotic used to treat TB
- first-line drug
inhibits RNA Polymerase
Isoniazid
antibiotic used to treat TB
- first-line drug
inhibits mycolic acid synthesis)
BCG
bacille Calmette-Guerin
- LIVING vaccine prepared from attenuated M. bovis
- no ESX-1 secretion system (less virulent)
- controversial due to variable efficacy for pulmonary TB
- effective agianst miliary TB
- vaccinated ppl can give a false positive for tuberculin test
recommended for ppl w/ high risk to exposure
Leprosy
- chronic disease caused by M. leprae
- also called Hansen’s disease
- very SLOW progression (incubation of about 5 years)
- can cause permanent damage to skin, nerves, limbs, eyes
- rare in high income countries
- mainly in tropical, developing countries
- victims have been ostracized
- lesions are visible
M. leprae
gram-POSITIVE acid fast, rod shaped, waxy cell envelope (mycolic acid)
- cannot be cultivated in vitro/labs
- infects macrophages of skin + Schwann cells in nerves
- can grow in foot pads of mice
- causes systemic infection in armadillo
Leprosy vs TB
- TB lesions are hidden while leprosy lesions are visible
- leprosy is much LESS infectious than TB
Major forms of Leprosy
Tuberculoid and Lepromatous
Tuberculoid Leprosy
- cell-mediated immunity present
- macrophage can contain bacteria
- light coloured lesions w/ anesthetic areas
- become tuberculin positive (active T cell-mediated responses)
Tuberculoid Leprosy can be self-limiting (immune system wins + kills pathogens)
Lepromatous Leprosy
- cell-mediated responses are ABSENT
- macrophages are NOT activated
- M. leprae survives and multiplies in macrophages + Schwann cells
- nerve damage + loss of sensation = inadvertent traumatic lesions on face + extremities
- can cause loss of eyebrows, thickening and enlarged ears and cheeks = LION-like appearance
- lesions can be secondarily infected = bone resorption, disfigurements and mutilation
Leprosy damage to nerve cells
damage to nerve cells is INDIRECT
- caused by MACROPHAGES
Spread and progression of Leprosy
- transmission is not well understood
- likely need direct contact for extended periods of time - inhaled droplets?
- most exposed individuals do not develop disease (host genetics are important)
Leprosy and antibiotics
Leprosy is treatable w/ antibiotics
- multidrug therapy (MDT) with 3 antibiotics
- 6 months to 1 year
- patients are thought to no longer transmit the diseases after one dose of MDT
- ultimate goal is elimination of leprosy
