World TB Day - March 24 th Mycobacterium tuberculosis Presented By: Haneen Oueis, Suzanne Midani, Rodney Rosfeld, Lisa Petty.

World TB Day - March 24th

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

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

Every year 8 million cases reported Every year 8 million cases reported annuallyannually

Death rate after contracting the disease, if Death rate after contracting the disease, if untreated, is the same as flipping a coinuntreated, 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 BCE have from 3500 BCE have the presence of the presence of Mycobacterium Mycobacterium tuberculosistuberculosis

The Great White PlagueThe Great White Plague

Started in Europe Started in Europe in 1600’sin 1600’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 sanitariums, which served as waiting served as waiting rooms for deathrooms for death

Disease progression- Stage Disease progression- Stage 11

Stage 1Stage 1 Droplet nuclei are inhaled, Droplet nuclei are inhaled,

and are generated by talking, and are generated by talking, coughing and sneezing.coughing and sneezing.

Once nuclei are inhaled, the Once nuclei are inhaled, the bacteria are non-specifically bacteria are non-specifically taken up by alveolar taken up by alveolar macrophages. macrophages.

The macrophages will not be The macrophages will not be activated, therefore unable to activated, therefore unable to destroy the intracellular destroy the intracellular organism.organism.

The large droplet nuclei The large droplet nuclei reaches upper respiratory reaches upper respiratory tract, and the small droplet tract, and the small droplet nuclei reaches air sacs of the nuclei reaches air sacs of the lung (alveoli) where infection lung (alveoli) where infection begins.begins.

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

Disease Progression- Stage Disease Progression- Stage 22

Begins after 7-21 days after initial infection.Begins 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

Lymphocytes, specifically T-cells recognize TB antigen. Lymphocytes, specifically T-cells recognize TB antigen. This results in T-cell activation and the release of This results in T-cell activation and the release of Cytokines, including interferon (IFN). 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 within low PH and anoxic environment, but TB can persist within these tubercles for extended periods. 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 these macrophages to replicate causing the tubercle TB uses these macrophages to replicate causing the tubercle to grow.to 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. infection which may spread to other parts of the lungs. Tubercle may also invade artery or other blood supply.Tubercle may also invade artery or other blood supply.

Spreading of TB may cause milliary tuberculosis, which can Spreading of TB may cause milliary 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.

Stage 5Stage 5 The caseous centers of the tubercles liquefy.The caseous centers of the tubercles liquefy.

This liquid is very crucial for the growth of TB, and This liquid is very crucial for the growth of TB, and therefore it multiplies rapidly (extracellularly).therefore it multiplies rapidly (extracellularly).

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

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

Virulent Mechanisms of TBVirulent Mechanisms of TB

TB mechanism for cell entryTB mechanism for cell entry The tubercle bacillus can bind directly to The tubercle bacillus can bind directly to

mannose receptors on macrophages via the cell mannose receptors on macrophages via the cell wall-associated mannosylated glycolipid (LAM)wall-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 from TB can remain in the phagosome or escape from

the phagosome ( Either case is a protected 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 alkaline Accounts for resistance to killing by acidic and alkaline

compounds in both the inracellular and extracelluar compounds in both the inracellular and extracelluar environmentenvironment

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

Antibiotic MechanismsAntibiotic Mechanisms

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

Problems with Mainstream Problems with Mainstream AntibioticsAntibiotics

• 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, bovis, M. tuberculosis, leprae, africanum, bovis,

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

Resistance Mechanisms of Resistance Mechanisms of TBTB

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

• Also, thru attenuation of catalase activity, in this Also, thru attenuation of catalase activity, in this way TB has developed resistance against way TB has developed resistance against certain drugs (asonizid)certain drugs (asonizid)

• TB microbe has accumulated mutations that TB microbe has accumulated mutations that resist antibiotic binding (rifampicin and resist antibiotic binding (rifampicin and derivatives)derivatives)

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

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

Without proper treatment, Without proper treatment, approximately 90% of those living with approximately 90% of those living with HIV die within months of contracting HIV die within months of contracting TB. 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

Individual infected with HIV has a 10 Individual infected with HIV has a 10 x increased risk in developing TBx increased risk in developing 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 M. infected with 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 CD4+ cells play an important role in the body’s defense against tubercle the body’s defense against tubercle bacillibacilli

Immune system becomes less able Immune system becomes less able to prevent growth and local spread to prevent growth and local spread of M. of 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 drugs People infected with TB that is resistant to first-line TB drugs will confer this resistant form of TB to people they infect. will confer this resistant form of TB to people they infect.

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

MDR-TB is rapidly becoming a problem in Russia, Central Asia, MDR-TB is rapidly becoming a problem in Russia, Central Asia, China, and India.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 tuber-culosis by DNA injection. Vaccination of tuber-culosis by DNA injection. Nature Medicine Volume 2, No. 8Nature Medicine Volume 2, No. 8

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