Transcript Stages of Tuberculosis

Mycobacterium tuberculosis
By: Lisa Petty, Haneen Oueis, Suzanne Midani,
Rodney Rosfeld
World TB Day - March 24th
Statistics
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#1 on the list of lethal infectious diseases
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2 million deaths worldwide annually
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8 million new cases reported annually
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Death rate after contracting the disease, if
untreated, is the same as flipping a coin
History
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TB has been known as
Pthisis, King’s Evil,
Pott’s disease,
consumption, and the
White Plague.
Egyptian mummies
from 3500 BC have
the presence of
Mycobacterium
tuberculosis
The Great White Plague
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Started in Europe in
1600’s
Reigned for around
200 years
Named for the loss of
skin color of those
infected
The New World
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Infected the New World
before the Europeans
10% deaths in the 19th
century were due to TB
Isolated the infected in
sanitariums, which only
served as waiting rooms
for death
Disease Progression – Stage 1
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Droplet nuclei are inhaled and
generated by talking, coughing and
sneezing.
Once nuclei are inhaled, bacteria
are taken up by alveolar
macrophages.
Macrophages remain inactivated
and are unable to destroy the
intracellular organism.
Droplet nuclei reach respiratory
tract and alveoli where infection
begins.
Disease onset when droplet nuclei
reach the alveoli.
Disease Progression – Stage 2
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Begins after 7-21 days after initial infection
TB multiplies within the inactivated
macrophages until macrophages burst.
Other macrophages diffuse from peripheral
blood, phagocytose TB and are inactivated,
rendering them unable to destroy TB.
Disease Progression – Stage 3
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T-cells recognize TB antigen, resulting in T-cell activation and
the release of cytokines, including interferon (IFN).
The release of IFN causes the activation of macrophages,
which can release lytic enzymes and reactive intermediates
that facilitates immune pathology.
Tubercle forms, which contains a semi-solid or “cheesy”
consistency. TB cannot multiply within tubercles due to low pH
and anoxic environment, but TB can persist within these
tubercles for extended periods.
Disease Progression – Stage 4
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Although many activated macrophages surround the tubercles,
many other macrophages are inactivated or poorly activated.
TB uses macrophages to replicate causing the tubercle to grow.
The growing tubercle may invade a bronchus, causing an infection
which may spread to other parts of the lungs or invade circulatory
system.
Spreading of TB may cause miliary tuberculosis, which can cause
secondary lesions.
Secondary lesions occur in bones, joints, lymph nodes, genitourinary
system and peritoneum.
Disease Progression – Stage 5
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The caseous centers of the tubercles liquefy.
Liquid is crucial for the TB’s growth, and therefore
it multiplies rapidly (extracellularly).
This later becomes a large antigen load, causing
the walls of nearby bronchi to become necrotic
and rupture.
This results in cavity formation and allows TB to
spread rapidly into other airways and to other
parts of the lung.
Virulent Mechanisms of TB
TB mechanism for cellular entry
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The tubercle bacillus binds directly to mannose
receptors on macrophages via the cell wallassociated mannosylated glycolipid (LAM).
TB can grow intracellularly
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Effective means of evading the immune system
Once TB is phagocytosed, it can inhibit
phagosome-lysosome fusion
TB can remain in the phagosome or escape from
the phagosome (Either case is a protected
environment for growth in macrophages)
Virulent Mechanisms of TB
Slow generation time
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Immune system cannot recognize TB or cannot be
triggered to eliminate TB
High lipid concentration in cell wall
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Accounts for impermeability and resistance to
antimicrobial agents
Accounts for resistance to killing by acidic and alkaline
compounds in both the intracellular and extracelluar
environment
Also accounts for resistance to osmotic lysis via
complement deposition and attack by lysozyme
Virulent Factors of TB
Antigen 85 complex
It is composed of proteins secreted by TB that
can bind to fibronectin.
 These proteins can aid in walling off the
bacteria from the immune system
Cord factor
 Associated with virulent strains of TB
 Toxic to mammalian cells
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Resistance Mechanisms of TB
•
TB inactivates drug by acetylation – effective on
aminoglycoside antibiotics (streptomycin)
•
Attenuation of catalase activity (asonizid)
•
Accumulated mutations resist antibiotic binding
(rifampicin and derivatives)
Problems with Mainstream
Antibiotics
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β–lactam inhibitors of peptidoglycan biosynthesis
is not effective due to protection by mycobacterial
long chain fatty acids (40 – 90 carbons) in plasma
lemma
•
Need unique target for mycobacterial species M. tuberculosis, leprae, africanum and bovis,
•
To solve antibiotic problem select something other
than a cellular wall disruptor
Antibiotic Mechanisms
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Inhibition of mRNA translation and
translational accuracy (streptomycin and
derivatives)
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RNA polymerase inhibition (rifampicin) –
inhibition of transcript elongation
•
Gyrase inhibition in DNA synthesis
(fluoroquinolone)
Antibiotic Mechanism II
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Inhibition of mycolic acid synthesis for
cellular wall (isoniazid)
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Inhibition of arabinogalactan synthesis for
cellular wall synthesis (ethambutol)
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Sterilization – by lowering pH
(pyrazinamide)
Antitubercular Pharmaceutics
“The co-epidemic”
HIV & TB
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HIV is the most powerful
factor known to increase the
risk of TB
HIV promotes both the
progression of latent TB
infection to active disease and
relapse of the disease in
previously treated patients.
TB is one of the leading
causes of death in HIVinfected people.
TB/HIV Facts
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Up to 70% of TB patients are co-infected with HIV in some
countries.
One-third of the 40 million people living with HIV/AIDS
worldwide are co-infected with TB.
Without treatment, approximately 90% of HIV patients die
within months of contracting TB.
HIV/AIDS is dramatically fuelling the TB epidemic in subSaharan Africa
TB/HIV Facts
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HIV+ individuals are 10x more likely to
develop TB
By 2000 nearly 11.5 million HIV-infected
people worldwide were co-infected with M.
tuberculosis
- 70% of these 11.5
million co-infection cases
were in sub-Saharan
Africa
Patterns of HIV-related TB
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As HIV infection progresses CD4+ T-lymphocytes
decline in number and function.
CD4+ cells play an important role in the body’s
defense against tubercle bacilli
Immune system becomes less able to prevent
growth and local spread of M. tuberculosis
Reasons for Fear
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Drug resistant strains of Mycobacterium
tuberculosis have developed
Underdeveloped countries are the most
affected by TB
95% of reported cases come from
underdeveloped countries
High HIV rates in those areas contribute to
the contraction of TB
What is MDR-TB ?
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It is a mutated form of the TB microbe that is extremely resistant to
at least the two most powerful anti-TB drugs - isoniazid and
rifampicin.
People infected with TB that is resistant to first-line TB drugs will
confer this resistant form of TB to others.
MDR-TB is treatable but requires treatment for up to 2 years.
MDR-TB is rapidly becoming a problem in Russia, Central Asia,
China, and India.
MDR-TB in the news:
Man with tuberculosis jailed as
threat to health
- USA Today 4-11-2007
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Russian-born man with extensively drugresistant strain of TB, has been locked in a
Phoenix hospital jail ward since July for not
wearing face mask
Citations
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Blanchard, J. 1996. Molecular mechanisms of drug
resistance in Mycobacterium tuberculosis. Annual
Review of Biochemistry 65:215-39
National Institute of Allergy and Infectious Diseases:
http://www.niaid.nih.gov/publications/blueprint/pag
e2.htm
Tascon, R., Colston, M. et al. 1996. Vaccination of
tuberculosis by DNA injection. Nature Medicine
Volume 2, No. 8
WHO HIV/TB Clinical Manual
http://whqlibdoc.who.int/publications/2004/9241
546344.pdf
http://www.scielo.br/img/revistas/mioc/v101n7/v1
01n7a01f02.gif
http://textbookofbacteriology.net/tuberculosis.html
http://efletch.myweb.uga.edu/history.htm
http://www.faculty.virginia.edu/blueridgesanatoriu
m/death.htm
http://www.gsk.com/infocus/whiteplague.htm