Tuberculosis M. tuberculosis - PowerPoint Presentation

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Tuberculosis

M. tuberculosis

Dr.

Mohed

Shaker

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A Brief History of Tuberculosis (TB)

Tuberculosis (phthisis) described since the time of

Hippocrates (460 BC - 370 BC)

1689: Doctor Richard Morton

used the term

“consumption” to denote TB.Second half of the 17th century: high death rates from TB in Europe.1722: Doctor Benjamin Marten proposed that TB could be transmitted in the air and described TB as being caused by “wonderfully minute living creatures”End of 19th century to the start of 20th century: Principal cause of death in Europe was TB.The romantic Era of TB

“Queen Guinevere” painted by William Morris

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A Brief History of Tuberculosis (TB)

1865 Jean-Antoine

Villemin

:

confirmed that

TB is contagious. Robert Koch:1882: Isolated and cultured M. tuberculosis.1890: Announced the discovery of tuberculin.Developed staining methods used to identify the bacteria.

1905: R

eceived

the Nobel Prize

Bacteriologist Paul Ehrlich developed Ziehl- Neelsen staining. Late 1800’s: Edward Livingston Trudeau established “Adirondack Cottage Sanatorium”, first TB sanatorium in the US.

Visualization of

M. tuberculosis

using the Ziehl-Neelsen stain

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1896 Theobald Smith

demonstrated that bovine TB is caused by M. bovis.

1908 Albert Calmette and

Camille Guérin

isolated

M. bovis and grew it in ox bile.Identified a morphological variant of M. bovis found to be avirulent, conferred immunity against M. tuberculosis.Lead to the BCG vaccine (bacilli Calmette-Guérin).Development of antibiotics to combat infection:1947: streptomycin, 1952: isoniazidThe majority of drugs used to combat infection were identified between 1945 and 1967.No new drugs developed since the 1980’s

Reoccurrence of TB for two main reasons:

1)HIV/AIDS pandemic

2)Development of drug resistance

A Brief History of Tuberculosis (TB)

M. bovis

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Reservoir:

HumansTransmission:

Airborne disease (aerosol transmission) Symptoms

:

Latent TB infection:

Active TB infection:No symptoms Bad cough *Cannot spread TB Coughing up blood/sputum Chest pain Loss of appetite Weight loss Fever Chills Night sweats Swollen glands *Contagious Tuberculosis in Humans

Extra-pulmonary TB

:

Symptoms depend on location of infection

General symptoms:

fatigue, fever, loss of appetite, weight loss.TB of lymph nodes: swelling of lymph nodesTB meningitis: neurological symptoms including headacheSpinal TB: Mobility impairments, pain

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Mycobacterium Tuberculosis

General Characteristics

Family – Myobacteria

Gram-positive aerobic rod-shaped bacilli

“Acid fast” bacteria

Lack of spore formation and toxin productionNo capsule, flagellum (non-motile)Generation time of 18- 24 hours but requires 3-4 weeks for visual coloniesPathological FeaturesPrinciple cause of Human TuberculosisIntracellular pathogen (alveolar macrophages)Waxy, thick, complex cellular envelope

Cell envelope components ex) sulfolipids

Produces

tubercles

, localized lesions of M. tuberculosis SEM of M. tuberculosisM. Tuberculosis (stained in purple)

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Mycobacterial Cellular Envelope

General Features

Thick, waxy and complex

Higher fluidity in more external regions than internal regions

Relatively impermeable to hydrophilic solutes

Contain porins (selective cationic channels)Main ComponentsPeptidoglycan  contains N-glycolylmuramic acid instead of N-acetylmuramic acid

Arabinogalactan

Mycolic

Acids (60% of cellular envelope)

Lipoarabinomannan

(LAM)

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Mycobacterial Cellular Envelope

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Contribution of Mycobacterial

Cellular Envelope to Pathogenesis

Resistance to Drying and Other Environmental Factors

Thick, waxy nature of cellular envelope protects M. tuberculosis from drying, alkali conditions, and chemical disinfectants

Hinders entrance of antimicrobial agents

Entry into Host Cells Lipoarabinomannan (LAM) binds to mannose receptors on alveolar macropages leading to entry into the cellInterference of Host Immune Response- Glycolipids and sulfolipids

decrease the effects of oxidative cytotoxic mechanism

Inhibition of

phagosome

and

lysosome fusion inside macrophageWaxy cellular envelope prevents acidification of the bacteria inside the phagosome

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Factors Affecting Pathogenicity

Active Infection

Only individuals with an active infection can transmit the disease

Transmission

Aerosolized droplets need to be <10

μm in order to evade the ciliated epithelium of the lung to establish infection in the terminal alveoliGrowth & StructureOnly require a very few number of bacteria to establish an infection (1-10 bacteria)Slow generation time M. Tuberculosis

in sputum

(stained in red)

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Variability of Infection Rates

Exposure Time

Most infected individuals expel relatively few bacilli, transmission of TB usually occurs only after prolonged exposure to someone with active TB.

On average, 50% of people are likely to become infected with TB if they spend 8hrs/day for six months or 24hrs/day for two months working or living with someone with active TB.

Health of Individuals

Active TB typically occur in individuals whose immune systems have been weakened by age, disease, improper nutrition or use of immunosuppresive drugs.

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Tuberculosis – Disease Progression

Primary Infection

In healthy individuals…

M. tuberculosis

phagocytosed by alveolar macrophages leading to intracellular proliferation and

tubercle formationCell-mediated response develops and eliminates most of the bacilli in 2-6 weeksCommonly asymptomaticORM. tuberculosis can remain dormant intracellularly

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Tuberculosis –

Disease

Progression

Primary Infection

Immunocomprimised

Individuals…Infection leads usually leads to progressive primary tuberculosis, where the pathogen breaks out of the tubercles in the alveoli and cause active diseaseActive disease leads to chronic inflammationDeath of pathogen and pulmonary cells can lead to Gohn complex and granuloma formationMay lead to extrapulmonary tuberculosis (TB infection outside the lung in the CNS and lymph nodes)

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Latent Tuberculosis Infections

Following exposure to TB: Inhaled bacilli usually destroyed by

host’s immune system

(90-95% of the time).

Healthy person: Recruitment of

T-cells and macrophages which results in controlling the infection.Some bacilli can establish infection in macrophages (phagosomes) leading to host immune responseBacilli forced into an inactive (latent), non-replicating state.Survive intracellularly: prevent phagosome-lysosome fusion

.

Infection contained but not eradicated.

The dormant bacteria are still viable, can be re-activated: Approximately 10% of latent infections will develop into active TB if left untreated.

Factors that lead to re-activation of the bacteria:

HIV co-infection, aging, cancer, diabetes etcM. Tuberculosis colonies

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Tuberculosis – Disease Progression

Note…

Infection does not mean disease!

Infection can lead to active disease or dormant state of pathogen

Active disease develops differently (Healthy individuals VS.

Immunocomprimised individuals)Summary of TB Infection in Alverolar Macrophageshttp://www.nature.com/nrmicro/animation/imp_animation/index.html

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Antibacterial chemotherapy

:Combination of first

and second line drugs for the first 2 months which could include:

Isoniazid

Rifampicin

PyrazinamideStreptomycin or EthambutolNext 4 months, combination of:IsoniazidRifampicinTreatment

Early resistance to

isoniazid

: other first-line drugs

such as

ethambutol, streptomycin, pyrazinamide and fluoroquinolones can be added to drug arsenal (treatment period also extended). These drugs are relatively effective in killing the bacteria, however, they also produce a wide variety of side effects.

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First line drugs:

- Bactericidal agents

: kill active bacteria, important in the early stages of infection.

Second line drugs:

-

Bacteriostatic: hinder bacterial growth.- Strengthen treatment in the case of resistant bacteria.- Less efficient and generally more toxic than first line drugs.Inappropriate chemotherapy:Monotherapy (single drug treatment)Decreased treatment periodLow absorption of drugs

Treatment

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Drug

Bactericidal or

Bacteriostatic

Mechanism of Action

Mutation Rate

Side Effects

Isoniazid

Bactericidal

to rapidly dividing bacteria and

bacteriostatic

to slowly dividing bacteria

Pro-drug: activated by a bacterial catalase.

Inhibits enoyl-ACP reductase (key enzyme in fatty acid synthesis, different than equivalent mammalian enzymes)

1 in 10

5

- 10

6

Rash, abnormal liver function, anemia, peripheral neuropathy, mild CNS effects

Rifampicin

Bactericidal

Inhibits transcription by RNA polymerase

1 in 10

8

Fever, immune reactions, GI irritation, liver damage, can cause tears and urine to turn red/orange

Streptomycin

Bactericidal

Inhibits initiation of protein synthesis

1 in 10

8

- 10

9

Damage to the ears, nausea, rash, vomiting, vertigo

Ethambutol

Bacteriostatic

Prevents formation of the cell wall

1 in 10

7

Decrease in visual acuity, colourblindness and other visual defects, joint pain, nausea, vomiting, fever, malaise, headache, dizziness

Fluoroquinolones

Bactericidal

Act manly on DNA gyrase (DNA gyrase: introduces negative supercoils into DNA)

Tendon damage, heart problems, swelling of face and throat, shortness of breath, rash, loss of consciouness

Pyrazinamide

Bacteriostatic,

Bactericidal

Accumuates causing cellular damage

Joint pain, nauseau, vomiting, rash, malaise, fever, photosentivity

Treatment

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M. tuberculosis:

naturally resistant to certain antibiotics due to presence of:Drug-modifying enzymes

Drug-efflux systemsHydrophobic cell wall

Mycobacteria undergo natural mutations which can lead to development of drug resistance.

TB is treated by administration of

combination chemotherapy: decreases probability of development of drug resistance.Development of increasingly resistant strains mainly due to: Patient non-complianceDrug Resistance and Tuberculosis

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MDR: Multidrug-resistant strains

:Strains of tuberculosis resistant at least to

rifampicin and isoniazid.

Mortality rate: 40-60%

Estimated that 50 million people are infected with MDR-TB.

MDR-TB is approximately 125 times more expensive to treat than drug susceptible TB.MDR and XDR TuberculosisXDR: Extensively-drug resistant strains: Strains of tuberculosis resistant to rifampicin, isoniazid and at least three of the following classes of second-line drugs: aminoglycosides, polypetides, fluoroquinolones, thioamides,

cycloserine and para-aminosalicylic acid

.

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Emergence due to lack of patient compliance during TB treatment and inappropriate administration of TB drugs.

Results in more aggressive forms of TB.

Drug resistance does not increase infectiousness. MDR and

XDR-TB

: uncommon in developing nations lacking TB drugs (high drug-susceptible TB rates)

MDR and XDR-TB rates are higher in developed nations with access to anti-TB drugs.MDR and XDR Tuberculosis

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HIV pandemic has reversed much of the progress made in the past few decades in combating TB.

People with latent TB have a 10-20%

of developing active TB in their lifetime. People with HIV and latent TB are 100 times more likely to develop active TB.

HIV/AIDS leads to a compromised

immune system:HIV infects CD4+ T cells, macrophages, dendritic cells.Result: decreased CD4+ T cells due to apoptosis of infected cells,

CD8+

T cell

mediated killing of infected cells

The numbers of

CD4+ T cells progressively decline (loss of cell-mediated immunity) and the body is much more susceptible to infectionTuberculosis and HIV/AIDST cell

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A person with HIV/AIDS will have a harder time fighting off the

M. tuberculosis infection due to a compromised immune system

.HIV infection can cause latent

M. tuberculosis

infection to become reactivated.

TB is the leading cause of death for people with HIV/AIDS: mean survival rate is 430 days.MDR and XDR-TB and HIV/AIDS:Additional symptoms: excessive weight loss, respiratory problems (including the formation of lesions in the lungs).Mean survival rate: 45 days. Tuberculosis and HIV/AIDS