LIFE CYCLE AND PATHOGENESIS OF Mycobacterium tuberculosis

Presented by

T.N.Jaya Ganesh

Cell and Molecular Biology

I - M.Sc Biotechnology

Dept. of Biotechnology

Bharathiar University.

INTRODUCTION

TB is an airborne disease caused by the bacterium Mycobacterium tuberculosis.

M. tuberculosis and seven very closely related mycobacterial species (M. bovis, M. africanum, M. microti, M. caprae, M. pinnipedii, M. canetti and M. mungi) together comprise what is known as the M. tuberculosis complex.

Most, but not all, of these species have been found to cause disease in humans. The majority of TB cases are caused by M. tuberculosis. M. tuberculosis

organisms are also called tubercle bacilli.

TB HISTORY TIMELINE

1840 19201860 1900 1940 1960 1980 20001880

1993: TB cases decline due to increased funding and enhanced

TB control efforts

Mid-1970s: Most TB sanatoriums in U.S. closed

1884: First TB

sanatorium established

in U.S.

1865: Jean-

Antoine Villemin

proved TB is contagious

1943: Streptomycin (SM) a drug

used to treat TB is discovered

1882: Robert Koch discovers

M. tuberculosis

Mid-1980s: Unexpected rise

in TB cases

1943-1952: Two more drugs

are discovered to treat TB: INH and

PAS

TB TRANSMISSION

TB TRANSMISSION

M. tuberculosis is carried in airborne particles, called droplet nuclei, of 1– 5 microns in diameter.

Infectious droplet nuclei are generated when persons who have pulmonary or laryngeal TB disease cough, sneeze, shout, or sing.

Depending on the environment, these tiny particles can remain suspended in the air for several hours.

M. tuberculosis is transmitted through the air, not by surface contact. Transmission occurs when a person inhales droplet nuclei containing M.

tuberculosis, and the droplet nuclei traverse the mouth or nasal passages, upper respiratory tract, and bronchi to reach the alveoli of the lungs.

TB TRANSMISSION (1)

TB is spread from person to person through the air. Dots in air represent droplet nuclei containing M. tuberculosis

TB TRANSMISSION (2)

Probability that TB will be transmitted depends on: Infectiousness of person with TB disease Environment in which exposure occurred Length of exposure Virulence (strength) of the tubercle bacilli

The best way to stop transmission is to: Isolate infectious persons Provide effective treatment to infectious persons as soon as

possible

M.tuberculosis (scanning EM) M.tuberculosis on Lowenstein-Jensen medium

LIFE CYCLEIt is an obligate aerobe and grow very slowly.

15-20 hour doubling vs. 30 minutes for E. coli.

It require 6-8 weeks to grow on plates

DRUG-RESISTANT TB

DRUG-RESISTANT TB (1)

Caused by M. tuberculosis organisms resistant to at least one TB treatment drug

Isoniazid (INH) Para-aminosalicylate sodium

(PAS) Rifampin (RIF) Pyrazinamide (PZA) Ethambutol (EMB)

Resistant means drugs can no longer kill the bacteria

DRUG-RESISTANT TB (2)

Primary ResistanceCaused by person-to-person transmission of drug-resistant organisms

Secondary Resistance

Develops during TB treatment:

• Patient was not given appropriate treatment regimen (OR)• Patient did not follow treatment regimen as prescribed

DRUG-RESISTANT TB (3)

Mono-resistantResistant to any one TB treatment drug

Poly-resistantResistant to at least any 2 TB drugs (but not both isoniazid and rifampin)

Multidrug resistant (MDR TB)

Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugs

Extensively drug resistant (XDR TB)

Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs (e.g., amikacin, kanamycin, or capreomycin)

TB PATHOGENESIS

LATENT TB INFECTION (LTBI)

Persons with LTBI have M. tuberculosis in their bodies, but do not have TB disease and cannot spread the infection to other people.

A person with LTBI is not regarded as having a case of TB. The process of LTBI begins when extracellular bacilli are ingested by

macrophages and presented to other white blood cells. This triggers the immune response in which white blood cells kill or

encapsulate most of the bacilli, leading to the formation of a granuloma. At this point, LTBI has been established.

TB DISEASE

In some people, the tubercle bacilli overcome the immune system and multiply, resulting in progression from LTBI to TB disease.

Persons who have TB disease are usually infectious and may spread the bacteria to other people.

The progression from LTBI to TB disease may occur at any time, from soon to

many years later.

TB PATHOGENESIS (1)

Droplet nuclei containing tubercle bacilli are inhaled, enter the

lungs, and travel to small air sacs (alveoli)

bronchio leblood vessel

tubercle bacilli

a lveoli

2

Tubercle bacilli multiply in alveoli, where

infection begins

TB PATHOGENESIS (2)

A small number of tubercle bacilli enter

bloodstream and spread throughout body

brain

lung

kidney

bone3 special

im m une cells form a barrier shell (in th isexam ple,bacilli arein the lungs)

4

• Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli

• These cells form a barrier shell that keeps the bacilli contained

and under control (LTBI)

TB PATHOGENESIS (3)

shell breaks down and tuberclebacilli escape

m ultip ly(in th is exam ple,TB d isease develops in the lungs)

and

5

• If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease

• This process can occur in different places in the body

LTBI VS. TB DISEASE

Latent TB Infection (LTBI) TB Disease (in the lungs)

Inactive, contained tubercle bacilli in the body

Active, multiplying tubercle bacilli in the body

TST or blood test results usually positive

TST or blood test results usually positive

Chest x-ray usually normal Chest x-ray usually abnormal

Sputum smears and cultures negative Sputum smears and cultures may be positive

No symptoms Symptoms such as cough, fever, weight loss

Not infectious Often infectious before treatment

Not a case of TB A case of TB

PROGRESSION FROM LTBI TO TB DISEASE (1)

Risk of developing TB disease is highest the first 2 years after infection.

People with LTBI can be given treatment to prevent them from developing TB disease.

Detecting TB infection early and providing treatment helps prevent new cases of TB disease.

PROGRESSION TO TB DISEASE (2)

People Exposed to TB

Not TB Infected

Latent TB Infection (LTBI)

Not Infectious

Positive TST or QFT-G test

result

Latent TB Infection

May go on to develop TB

disease

Not Infectious

Negative TST or QFT-G test

result

No TB Infection

Figure 1.5

PROGRESSION TO TB DISEASE (4) TB AND HIVIn an HIV-infected person,TB can develop in one oftwo ways:

Person with LTBI becomes infected with HIV and then develops TB disease as the immune system is weakened

Person with HIV infection becomes infected with M. tuberculosis and then rapidly develops TB disease

SITES OF TB DISEASE (1)

Bacilli may reach any part of the body, but common sites include:

Brain

Lym ph node

Pleura

Lung

SpineKidney

Bone

Larynx

SITES OF TB DISEASE (2)Location Frequency

Pulmonary TB Lungs Most TB cases are pulmonary

Extrapulmonary TB

Places other than lungs such as:• Larynx• Lymph nodes• Pleura• Brain• Kidneys• Bones and joints

Found more often in:

• HIV-infected or other immunosuppressed persons

• Young children

Miliary TBCarried to all parts of body, through bloodstream

Rare

TB CLASSIFICATION SYSTEM (1)

Class Type Description

0 No TB exposureNot infected

No history of TB exposureNegative result to a TST or IGRA

1 TB exposureNo evidence of infection

History of TB exposureNegative result to a TST (given at least 8-10 weeks after exposure) or IGRA

2 TB infection No TB disease

Positive result to a TST or IGRA Negative smears and cultures (if done)No clinical or x-ray evidence of activeTB disease

Based on pathogenesis of TB

TB CLASSIFICATION SYSTEM (2)

Class

Type Description

3 TB, clinically active

Positive culture (if done) for M. tuberculosis Positive result to a TST and clinical, bacteriological, or x-ray evidence of TB disease

4 Previous TB disease(not clinically active)

Medical history of TB diseaseAbnormal but stable x-ray findings Positive result to a TST Negative smears and cultures (if done)No clinical or x-ray evidence of active TB disease

5 TB suspected Signs and symptoms of TB disease, but evaluation not complete

Based on pathogenesis of TB

DIAGNOSIS AND TREATMENT

LABORATORY DIAGNOSIS OF MYCOBACTERIAL DISEASE

Detection:Skin test – using PPD

MicroscopyCarbolfuchsin acid fast stainDirect nucleic acid probes

CultureSolid agar based or egg-based mediaBroth based media

Identification:Morphologic propertiesBiochemical propertiesAnalysis of cell wall lipidsNucleic acid probesNucleic acid sequencing

TREATMENT PREVENTION AND CONTROL

Multiple-drug regimens and prolonged treatment are required to prevent development of drug resistant strains.

Regimens recommended for treatment include isoniazid and rifampin for 9 months, with pyrazinamide and ethambutol or streptomycin added for drug resistance strains.

Prophylaxis for exposure to tuberculosis can include isoniazid for 9 months, rifampin for 4 months, or rifampin and pyrazinamide for 2 months.

Pyrazinamide and ethambutol or levofloxacin are used for 6 to 12 following exposure to drug-resistant M.tuberculosis.

Immunoprophylaxis with BCG in endemic countries.

Control of disease through active surveillance, prophylactic and therapeutic intervention, and careful case monitoring.

CONCLUSION

TB is easily tranmissable.

Curable under proper medication.

Preventive measures are the convienient way.

THANK YOU