World TB Day - March 24th

Mycobacterium tuberculosis By: Lisa Petty, Haneen Oueis, Suzanne Midani, Rodney Rosfeld

StatisticsStatistics #1 on the list of lethal infectious diseases #1 on the list of lethal infectious diseases

2 million deaths worldwide annually2 million deaths worldwide annually

8 million new cases reported annually8 million new cases reported annually

Death rate after contracting the disease, Death rate after contracting the disease, if untreated, is the same as flipping a coinif untreated, is the same as flipping a coin

HistoryHistory

TB has been known TB has been known as Pthisis, King’s as Pthisis, King’s Evil, Pott’s disease, Evil, Pott’s disease, consumption, and consumption, and the White Plague.the White Plague.

Egyptian mummies Egyptian mummies from 3500 BC have from 3500 BC have the presence of the presence of Mycobacterium Mycobacterium tuberculosistuberculosis

The Great White PlagueThe Great White Plague

Started in Europe in Started in Europe in 1600’s1600’s

Reigned for around Reigned for around 200 years200 years

Named for the loss Named for the loss of skin color of of skin color of those infectedthose infected

The New WorldThe New World Infected the New World Infected the New World

before the Europeansbefore the Europeans

10% deaths in the 1910% deaths in the 19thth century were due to TBcentury were due to TB

Isolated the infected in Isolated the infected in sanitariums, which only sanitariums, which only served as waiting served as waiting rooms for deathrooms for death

Disease Progression – Stage Disease Progression – Stage 11

Droplet nuclei are inhaled and Droplet nuclei are inhaled and generated by talking, coughing generated by talking, coughing and sneezing.and sneezing.

Once nuclei are inhaled, Once nuclei are inhaled, bacteria are taken up by bacteria are taken up by alveolar macrophages. alveolar macrophages.

Macrophages remain Macrophages remain inactivated and are unable to inactivated and are unable to destroy the intracellular destroy the intracellular organism.organism.

Droplet nuclei reach Droplet nuclei reach respiratory tract and alveoli respiratory tract and alveoli where infection begins.where infection begins.

Disease onset when droplet Disease onset when droplet nuclei reach the alveoli.nuclei reach the alveoli.

Disease Progression – Stage Disease Progression – Stage 22

Begins after 7-21 days after initial infectionBegins after 7-21 days after initial infection

TB multiplies within the inactivated TB multiplies within the inactivated macrophages until macrophages burst. macrophages until macrophages burst.

Other macrophages diffuse from peripheral Other macrophages diffuse from peripheral blood, phagocytose TB and are inactivated, blood, phagocytose TB and are inactivated, rendering them unable to destroy TB.rendering them unable to destroy TB.

Disease Progression – Stage Disease Progression – Stage 33

T-cells recognize TB antigen, resulting in T-cell activation T-cells recognize TB antigen, resulting in T-cell activation and the release of cytokines, including interferon (IFN). and the release of cytokines, including interferon (IFN).

The release of IFN causes the activation of macrophages, The release of IFN causes the activation of macrophages, which can release lytic enzymes and reactive which can release lytic enzymes and reactive intermediates that facilitates immune pathology.intermediates that facilitates immune pathology.

Tubercle forms, which contains a semi-solid or “cheesy” Tubercle forms, which contains a semi-solid or “cheesy” consistency. TB cannot multiply within tubercles due to consistency. TB cannot multiply within tubercles due to low pH and anoxic environment, but TB can persist low pH and anoxic environment, but TB can persist within these tubercles for extended periods. within these tubercles for extended periods.

Disease Progression – Stage Disease Progression – Stage 44 Although many activated macrophages surround the Although many activated macrophages surround the

tubercles, many other macrophages are inactivated or poorly tubercles, many other macrophages are inactivated or poorly activated.activated.

TB uses macrophages to replicate causing the tubercle to TB uses macrophages to replicate causing the tubercle to grow.grow.

The growing tubercle may invade a bronchus, causing an The growing tubercle may invade a bronchus, causing an infection which may spread to other parts of the lungs or infection which may spread to other parts of the lungs or invade circulatory system.invade circulatory system.

Spreading of TB may cause miliary tuberculosis, which can Spreading of TB may cause miliary tuberculosis, which can cause secondary lesions.cause secondary lesions.

Secondary lesions occur in bones, joints, lymph nodes, Secondary lesions occur in bones, joints, lymph nodes, genitourinary system and peritoneum. genitourinary system and peritoneum.

Disease Progression – Stage Disease Progression – Stage 55

The caseous centers of the tubercles liquefy.The caseous centers of the tubercles liquefy.

Liquid is crucial for the TB’s growth, and Liquid is crucial for the TB’s growth, and therefore it multiplies rapidly therefore it multiplies rapidly (extracellularly).(extracellularly).

This later becomes a large antigen load, This later becomes a large antigen load, causing the walls of nearby bronchi to causing the walls of nearby bronchi to become necrotic and rupture.become necrotic and rupture.

This results in cavity formation and allows TB This results in cavity formation and allows TB to spread rapidly into other airways and to to spread rapidly into other airways and to other parts of the lung.other parts of the lung.

Virulent Mechanisms of TBVirulent Mechanisms of TBTB mechanism for cellular entryTB mechanism for cellular entry

The tubercle bacillus binds directly to mannose The tubercle bacillus binds directly to mannose receptors on macrophages via the cell wall-receptors on macrophages via the cell wall-associated mannosylated glycolipid (LAM).associated mannosylated glycolipid (LAM).

TB can grow intracellularlyTB can grow intracellularly Effective means of evading the immune systemEffective means of evading the immune system Once TB is phagocytosed, it can inhibit Once TB is phagocytosed, it can inhibit

phagosome-lysosome fusionphagosome-lysosome fusion TB can remain in the phagosome or escape TB can remain in the phagosome or escape

from the phagosome (Either case is a protected from the phagosome (Either case is a protected environment for growth in macrophages)environment for growth in macrophages)

Virulent Mechanisms of TBVirulent Mechanisms of TB

Slow generation timeSlow generation time Immune system cannot recognize TB or cannot be Immune system cannot recognize TB or cannot be

triggered to eliminate TBtriggered to eliminate TB

High lipid concentration in cell wallHigh lipid concentration in cell wall Accounts for impermeability and resistance to Accounts for impermeability and resistance to

antimicrobial agentsantimicrobial agents Accounts for resistance to killing by acidic and Accounts for resistance to killing by acidic and

alkaline compounds in both the intracellular and alkaline compounds in both the intracellular and extracelluar environmentextracelluar environment

Also accounts for resistance to osmotic lysis via Also accounts for resistance to osmotic lysis via complement deposition and attack by lysozymecomplement deposition and attack by lysozyme

Virulent Factors of TBVirulent Factors of TB

Antigen 85 complexAntigen 85 complex It is composed of proteins secreted by It is composed of proteins secreted by

TB that can bind to fibronectin. TB that can bind to fibronectin. These proteins can aid in walling off the These proteins can aid in walling off the

bacteria from the immune systembacteria from the immune system

Cord factorCord factor Associated with virulent strains of TBAssociated with virulent strains of TB Toxic to mammalian cellsToxic to mammalian cells

Resistance Mechanisms of Resistance Mechanisms of TBTB

• TB inactivates drug by acetylation – TB inactivates drug by acetylation – effective on aminoglycoside antibiotics effective on aminoglycoside antibiotics (streptomycin)(streptomycin)

• Attenuation of catalase activity (asonizid)Attenuation of catalase activity (asonizid)

• Accumulated mutations resist antibiotic Accumulated mutations resist antibiotic binding (rifampicin and derivatives)binding (rifampicin and derivatives)

Problems with Mainstream Problems with Mainstream Antibiotics Antibiotics

• ββ–lactam inhibitors of peptidoglycan –lactam inhibitors of peptidoglycan biosynthesis is not effective due to protection biosynthesis is not effective due to protection by mycobacterial long chain fatty acids (40 – 90 by mycobacterial long chain fatty acids (40 – 90 carbons) in plasma lemmacarbons) in plasma lemma

• Need unique target for mycobacterial species - Need unique target for mycobacterial species - M. tuberculosis, leprae, africanum M. tuberculosis, leprae, africanum andand bovis, bovis,

• To solve antibiotic problem select something To solve antibiotic problem select something other than a cellular wall disruptorother than a cellular wall disruptor

Antibiotic MechanismsAntibiotic Mechanisms

• Inhibition of mRNA translation and Inhibition of mRNA translation and translational accuracy (streptomycin and translational accuracy (streptomycin and derivatives)derivatives)

• RNA polymerase inhibition (rifampicin) – RNA polymerase inhibition (rifampicin) – inhibition of transcript elongation inhibition of transcript elongation

• Gyrase inhibition in DNA synthesis Gyrase inhibition in DNA synthesis (fluoroquinolone) (fluoroquinolone)

Antibiotic Mechanism IIAntibiotic Mechanism II

• Inhibition of mycolic acid synthesis for Inhibition of mycolic acid synthesis for cellular wall (isoniazid)cellular wall (isoniazid)

• Inhibition of arabinogalactan synthesis Inhibition of arabinogalactan synthesis for cellular wall synthesis (ethambutol)for cellular wall synthesis (ethambutol)

• Sterilization – by lowering pH Sterilization – by lowering pH (pyrazinamide)(pyrazinamide)

Antitubercular Antitubercular PharmaceuticsPharmaceutics

““The co-epidemic”The co-epidemic”HIV & TBHIV & TB

HIV is the most powerful HIV is the most powerful factor known to increase factor known to increase the risk of TBthe risk of TB

HIV promotes both the HIV promotes both the progression of latent TB progression of latent TB infection to active disease infection to active disease and relapse of the disease and relapse of the disease in previously treated in previously treated patients. patients.

TB is one of the leading TB is one of the leading causes of death in HIV-causes of death in HIV-infected peopleinfected people. .

Up to 70% of TB patients are co-infected with Up to 70% of TB patients are co-infected with HIV in some countries. HIV in some countries.

One-third of the 40 million people living with One-third of the 40 million people living with HIV/AIDS worldwide are co-infected with TB.HIV/AIDS worldwide are co-infected with TB.

Without treatment, approximately 90% of Without treatment, approximately 90% of HIV patients die within months of HIV patients die within months of contracting TB. contracting TB.

HIV/AIDS is dramatically fuelling the TB HIV/AIDS is dramatically fuelling the TB epidemic in sub-Saharan Africaepidemic in sub-Saharan Africa

TB/HIV FactsTB/HIV Facts

TB/HIV FactsTB/HIV Facts

HIV+ individuals are 10x more likely HIV+ individuals are 10x more likely to develop TBto develop TB

By 2000 nearly 11.5 million HIV-By 2000 nearly 11.5 million HIV-infected people worldwide were co-infected people worldwide were co-infected with infected with M.M. tuberculosistuberculosis

- 70% of these 11.5 million co-infection cases were in sub-Saharan Africa

Patterns of HIV-related TBPatterns of HIV-related TB

As HIV infection progresses CD4+ T-As HIV infection progresses CD4+ T-lymphocytes decline in number and lymphocytes decline in number and function. function.

CD4+ cells play an important role in the CD4+ cells play an important role in the body’s defense against tubercle bacillibody’s defense against tubercle bacilli

Immune system becomes less able to Immune system becomes less able to prevent growth and local spread of prevent growth and local spread of M.M. tuberculosistuberculosis

Reasons for FearReasons for Fear

Drug resistant strains of Drug resistant strains of Mycobacterium Mycobacterium tuberculosistuberculosis have developed have developed

Underdeveloped countries are the most Underdeveloped countries are the most affected by TBaffected by TB

95% of reported cases come from 95% of reported cases come from underdeveloped countriesunderdeveloped countries

High HIV rates in those areas contribute High HIV rates in those areas contribute to the contraction of TBto the contraction of TB

What is MDR-TB ?What is MDR-TB ?

It is a mutated form of the TB microbe that is extremely It is a mutated form of the TB microbe that is extremely resistant to at least the two most powerful anti-TB drugs - resistant to at least the two most powerful anti-TB drugs - isoniazid and rifampicin.isoniazid and rifampicin.

People infected with TB that is resistant to first-line TB People infected with TB that is resistant to first-line TB drugs will confer this resistant form of TB to others.drugs will confer this resistant form of TB to others.

MDR-TB is treatable but requires treatment for up to 2 MDR-TB is treatable but requires treatment for up to 2 years. years.

MDR-TB is rapidly becoming a problem in Russia, Central MDR-TB is rapidly becoming a problem in Russia, Central Asia, China, and India.Asia, China, and India.

MDR-TB in the news:MDR-TB in the news:Man with tuberculosis jailed as Man with tuberculosis jailed as

threat to health threat to health - USA Today - USA Today 4-11-20074-11-2007

Russian-born man with extensively Russian-born man with extensively drug-resistant strain of TB, has been drug-resistant strain of TB, has been locked in a Phoenix hospital jail ward locked in a Phoenix hospital jail ward since July for not wearing face masksince July for not wearing face mask

CitationsCitations• 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/page2.htm

• Tascon, R., Colston, M. et al. 1996. Tascon, R., Colston, M. et al. 1996. Vaccination of tuberculosis by DNA injection. Vaccination of tuberculosis by DNA injection. Nature Medicine Volume 2, No. 8Nature Medicine Volume 2, No. 8

• WHO HIV/TB Clinical Manual WHO HIV/TB Clinical Manual http://whqlibdoc.who.int/publications/2004/92http://whqlibdoc.who.int/publications/2004/9241546344.pdf41546344.pdf

• http://www.scielo.br/img/revistas/mioc/v101n7/v101n7a01f02.gif

• http://textbookofbacteriology.net/tuberculosishttp://textbookofbacteriology.net/tuberculosis.html.html

• http://efletch.myweb.uga.edu/history.htmhttp://efletch.myweb.uga.edu/history.htm • http://www.faculty.virginia.edu/blueridgesanahttp://www.faculty.virginia.edu/blueridgesana

torium/death.htmtorium/death.htm• http://www.gsk.com/infocus/whiteplague.htmhttp://www.gsk.com/infocus/whiteplague.htm