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Tag words: tuberculosis, TB, Mycobacterium tuberculosis, M. tuberculosis, Mycobacterium bovis, Mycobacterium leprae, M.TB, MTB, Ziehl-Neelsen, cord factor, mycolic acid, granulomateous, tubercle, Simon foci, Ghon complex, tuberculin, PPD, tuberculin test, Mantoux test, skin test, isoniazid, INH, ethambutol, pyrazinamide, PZA, BCG vaccine, MDR TB, XDR TB.

Mycobacterium tuberculosis

Kingdom: Bacteria
Phylum: Actinobacteria
Order: Actinomycetales
Suborder: Corynebacterineae
Family: Mycobacteriaceae
Genus: Mycobacterium
Species: M. tuberculosis

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Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interest include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Mycobacterium tuberculosis and Tuberculosis (page 2)

(This chapter has 4 pages)

© Kenneth Todar, PhD

The Disease Tuberculosis

TB infection means that MTB is in the body, but the immune system is keeping the bacteria under control. The immune system does this by producing macrophages that surround the tubercle bacilli. The cells form a hard shell that keeps the bacilli contained and under control. Most people with TB infection have a positive reaction to the tuberculin skin test.  People who have TB infection but not TB disease are NOT infectious, i.e., they cannot spread the infection to other people. These people usually have a normal  chest x-ray. TB infection is not considered a case of TB disease. Major similarities and differences between TB infection and TB disease are given in the table below.

Tuberculosis: Infection vs Disease
TB Infection TB disease in lungs
MTB present MTB present
Tuberculin skin test positive Tuberculin skin test positive
Chest X-ray normal Chest X-ray usually reveals lesion
Sputum smears and cultures negative Sputum smears and cultures positive
No symptoms Symptoms such as cough, fever, weight loss
Not infectious  Often infectious before treatment
Not defined as a case of TB Defined as a case of TB

Predisposing factors for TB infection include:
- Close contact with large populations of people, i.e., schools, nursing homes, dormitories, prisons, etc.
- Poor nutrition
- iv drug use
- Alcoholism
- HIV infection is the #1 predisposing factor for MTB infection. 10 percent of all HIV-positive individuals harbor MTB. This is 400-times the rate associated with the general public

Only 3-4% of infected individuals will develop active disease upon initial infection, 5-10% within one year. These percentages are much higher if the individual is HIV+.

Stages of the Disease

The following stages that will be explained are for a MTB - sensitive host. It should be realized that, as stated previously, only a small percent of MTB infections progress to disease and even a smaller percent progress all the way to stage 5. Usually the host will control the infection at some point.

Disease progression depends on:
- Strain of MTB
- Prior exposure
- Vaccination
- Infectious dose
- Immune status of the host

Stage 1

Droplet nuclei are inhaled. One droplet nuclei contains no more than 3 bacilli. Droplet nuclei are so small that they can remain air-borne for extended periods of time. The most effective (infective) droplet nuclei tend to have a diameter of 5 micrometers. Droplet nuclei are generated by during talking coughing and sneezing.  Coughing generates about 3000 droplet nuclei. Talking for 5 minutes generates 3000 droplet nuclei but singing generates 3000 droplet nuclei in one minute. Sneezing generates the most droplet nuclei by far, which can spread to individuals up to 10 feet away.

Spread of droplet nuclei from one individual to another. CDC. After droplet nuclei are inhaled, the bacteria are nonspecifically taken up by alveolar macrophages. However, the macrophages are not activated and are unable to destroy the intracellular organisms.

Tuberculosis begins when droplet nuclei reach the alveoli. When a person inhales air that contains droplets most of the larger droplets become lodged in the upper respiratory tract (the nose and throat), where infection is unlikely to develop. However, the smaller droplet nuclei may reach the small air sacs of the lung (the alveoli), where infection begins.

Stage 2

Begins 7-21 days after initial infection. MTB multiplies virtually unrestricted within unactivated macrophages until the macrophages burst. Other macrophages begin to extravasate from peripheral blood. These macrophages also phagocytose MTB, but they are also unactivated and hence can not destroy the bacteria.

Stage 3

At this stage lymphocytes begin to infiltrate. The lymphocytes, specifically T-cells, recognize processed and presented MTB antigen in context of MHC molecules. This results in T-cell activation and the liberation of cytokines including gamma interferon (IFN). The liberation of IFN causes in the activation of macrophages. These activated macrophages are now capable of destroying MTB.

It is at this stage that the individual becomes tuberculin-positive. This positive tuberculin reaction is the result of the host developing a vigorous cell mediated immune (CMI) response. A CMI response must be mounted to control an MTB infection. An antibody mediated immune (AMI) will not aid in the control of a MTB infection because MTB is intracellular and if extracellular, it is resistant to complement killing due to the high lipid concentration in its cell wall.

Although a CMI response is necessary to control an MTB infection, it is also responsible for much of the pathology associated with tuberculosis. Activated macrophages may release lytic enzymes and reactive intermediates that facilitate the development of immune pathology. Activated macrophages and T-cells also secrete cytokines that may also play a role in the development of immune pathology, including Interleukin 1 ( IL-l), tumor necrosis factor (TNF), and gamma IFN.

It is also at this stage that tubercle formation begins. The center of the tubercle is characterized by "caseation necrosis", meaning it takes on a semi-solid or "cheesy" consistency. MTB cannot multiply within these tubercles because of the low pH and anoxic environment. MTB can, however, persist within these tubercles for extended periods.

Stage 4

Although many activated macrophages can be found surrounding the tubercles, many other macrophages present remain unactivated or poorly activated. MTB uses these macrophages to replicate, and hence, the tubercle grows.

The growing tubercle may invade a bronchus. If this happens, MTB infection can spread to other parts of the lung. Similarly the tubercle may invade an artery or other blood supply line. The hematogenous spread of MTB may result in extrapulmonary tuberculosis otherwise known as milliary tuberculosis. The name "milliary" is derived from the fact that metastasizing tubercles are about the same size as a millet seed, a grain commonly grown in Africa.

The secondary lesions caused by milliary TB can occur at almost any anatomical location, but usually involve the genitourinary system, bones, joints, lymph nodes and peritoneum. These lesions are of two types:

1. Exudative lesions result from the accumulation of PMN's around MTB. Here the bacteria replicate with virtually no resistance. This situation gives rise to the formation of a "soft tubercle".

2. Productive or granulomatous lesions occur when the host becomes hypersensitive to tuberculoproteins. This situation gives rise to the formation of a "hard tubercle".

Stage 5

For unknown reasons, the caseous centers of the tubercles liquefy. This liquid is very conducive to MTB growth, and the organism begins to rapidly multiply extracellularly. After time, the large antigen load causes the walls of nearby bronchi to become necrotic and rupture. This results in cavity formation. This also allows MTB to spill into other airways and rapidly spread to other parts of the lung.

As stated previously, only a very small percent of MTB infections result in disease, and even a smaller percentage of MTB infections progress to an advanced stage. Usually the host will begin to control the infection at some point. When the primary lesion heals, it becomes fibrous and calcifies. When this happens the lesion is referred to as the Ghon complex. Depending on the size and severity, the Ghon complex may never subside. Typically, the Ghon complex is readily visible upon chest X-ray.

Small metastatic foci containing low numbers of MTB may also calcify. However, in many cases these foci will contain viable organisms. These foci are referred to Simon foci. The Simon foci are also visible upon chest X-ray and are often the site of disease reactivation.

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Kenneth Todar has taught microbiology to undergraduate students at The University of Texas, University of Alaska and University of Wisconsin since 1969.

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