Tuberculosis and Other Mycobacteria Donald E Gardner PhD Fellow ATS

3 The Organisms

Human TB is caused by Mycobacterium tuberculosis var. hominis. The genus Mycobacterium is the only genus in the family Mycobacteriaceae and is represented by various pathogenic species, which characteristically produce chronic granulomatous lesions. Although the genus Mycobacterium includes other obligate parasites, saprophytes, and opportunistic pathogens that live freely in soil and water, the major ecological niche for M. tuberculosis is the tissue of humans and other warmblooded animals. The following section contains a description of some of the important species of Mycobacterium. The reader can consult various text and review articles for additional information about these organisms (5, 16-20).

These bacilli are straight or slightly curved, rod-shaped organisms. They vary from about 0.20.6 mm wide, and from 1-10 mm long, occasionally occurring as filaments but rarely branching. On the surface of a liquid media, their growth appears mold-like. The name "myco" suggests fungus-like and was derived because they occasionally exhibit filamentous or mycelium-like growth. These organisms are aerobic, nonmotile, and nonspore forming. Although mycobacteria have previously been described as unencapsulated organisms, recent electron microscopic data have provided evidence that pathogenic Mycobacterium has a capsule that aids in protecting the cells from the activities of the host's alveolar macrophages (21). These bacilli are very resistant to drying, thus increasing their ability to remain viable during prolonged stays outside the body. This resistance to drying is due to the large amounts of complex long-chain lipids (C78-C90) in their cell walls (40% of total cell dry weight). This high lipid content is also responsible for the fact that mycobacterial cells are difficult to stain by conventional methods, and once stained, they resist decolorization by either 95% ethanol or 3% hydrochloric acid. All mycobacteria have this characteristic and are often referred to as "acid-fast." Acid fastness is the most important characteristic of a mycobacterium because it can be used to differentiate these types of bacteria from other organisms. Mycobacterium species are euphemistically also referred to as "red snappers" because they appear red when stained and appear to break sharply when they reproduce. Another important component of the cell wall of these organisms is trehalose dimycolate, an indicator of the virulence of the organism. When this is present, the virulent strains tend to grow in a characteristic "serpentine" cord-like pattern in an artificial medium, where avirulent strains do not (22).

Because the great majority of Mycobacterium can be cultured on artificial media, these organisms are not considered obligate parasites. The major exception is M. leprae which has not been cultured on artificial media but grows only in certain animal or tissue cultures of macrophages. Growth rates for these organisms in culture range from slow to very slow. The transport of nutrients into the cell through the lipid layer in the cell wall is very slow, which is a factor in the slow growth rate of these organisms. It sometimes takes weeks for a visible colony to form. Waxes that make up the cell wall of these organisms also play a major role in their pathogencity and aids them in resisting digestion by phagocytes. In fact, this organism can actually multiply inside phagocytes.

Except for M. leprae, the Mycobacterium are classified into two broad categories—typical (e.g., M. tuberculosis, M. bovis, and M. africanum) and atypical which includes virually all the other species. All of these various members of Mycobacterium are closely related on the basis of DNA homology (23). The different organisms can be separated and identified by their growth rate, pigmentation in the light or dark, catalase and niacin production, nitrate and tellurite reduction, and Tween 80 hydrolysis. They have also been called MOTT (Mycobacteria other than tuberculosis). These atypical mycobacteria cause diseases that mimic TB and are clinically, roentgenographically, and pathologically identical to the disease produced by M. tuberculosis, except for one major difference. These infections are usually not communicable. In most cases, the causative agent can be differentiated from tuberculosis only by culturing the organism (24).

Mycobacterium africanum causes TB in tropical Africa; M. bovis causes TB in cattle, and it is highly virulent in humans and other primates, certain carnivores (e.g., dogs, cats, and swine), parrots, and some birds of prey. The organism is a bit shorter and plumper than M. tuberculosis, but the difference is slight. The disease produced in humans is virtually indistinguishable from that caused by M. tuberculosis var. hominis and is treated similarly (25). However, there are some differences between these two organisms. For example, M. bovis is highly pathogenic in rabbits, whereas M. tuberculosis is much less so. In culture, M. bovis tends to grow more slowly and cannot tolerate as high a concentration of glycerol. Serological tests and skin tests, however, cannot be used to differentiate between the two organisms.

Drinking unpasteurized milk and other dairy products from tuberculous cows has been responsible for much human TB. The ingested organisms presumably penetrate the mucosa of the oropharynx and intestines and give rise to early lesions in the cervical or mesenteric lymph nodes. Subsequent dissemination from these sites infects principally bones and joints. Such infection of vertebrae was largely responsible for the hunchbacks in previous generations. When inhaled (e.g., dairy farmers), the organism can also cause human pulmonary tuberculosis. TB due to M. bovis has now become very rare in many countries as a result of widespread pasteurization of milk and the elimination of tuberculosis in cattle.

In poultry and swine M. avium is an important cause of disease and can also infect humans. It was first recognized in the 1800s as the causative agent of a disease in chickens, but was not recognized as a cause of human disease until 1943. These organisms, which are collectively known as M. avian complex (MAC) are ubiquitous in nature and have been isolated from water, soil, plants, house dust, and a myriad of other environmental sources. These organisms usually have low pathogenicity and frequently colonize in individuals without causing disease. Human cases of MAC infection, unrelated to AIDS, occur more frequently in farming populations than in urban patients. The risk of contracting M. avium disease is very high among HIV + individuals. Lung infections caused by MAC most often occur in individuals (primarily men) who are smokers, whose lungs have been damaged by an old tuberculosis infection, bronchitis, or emphysema, or who have AIDS (14). There seems to be a clear difference in the disease pattern for the different types of mycobacterial infection in AIDS patients. Exposure to the usual human strain of TB seems to be related to an early onset of the disease in HIV + individuals, whereas the M. avium strain emerges only in the later stages of the disease (26). There has been speculation that there are different levels of immunity against the two organisms (i.e., an immunocompetent host, in general, can better control the growth of M. avium than M. tuberculosis) (25).

Some mycobacteria grow in swimming pools and even in aquariums. Aquarium workers and fishermen are at risk of being exposed to M. marianum, an organism that is associated with fish

(swimmer's granuloma). The site of this infection is primarily soft tissue, usually of the extremity.

Leprosy (Hansen's disease) is a chronic infectious disease caused by M. leprae, which has a unique tropism for two tissues—peripheral nerves and skin. The World Health Organization estimates that the global prevalence of leprosy is 10-12 million and the majority of cases occur in Asia and Africa. M. leprae is virtually indistinguishable in morphology and staining properties from M. tuberculosis and has many clinical features in common with TB. BecauseM. leprae has never been cultured successfully in vitro, it appears to be an obligate intracellular pathogen that requires the environment of the host macrophage for survival and propagation. This bacillus resists intracellular degradation by macrophages, perhaps by escaping from the phagosome into the cytoplasm, where it can accumulate to high levels (1010 bacilli/g of tissue) in lepromatous leprosy.

In voles, guinea pigs, rabbits, and calves, M. microti are associated with TB lesions. Other species such as muris and piscium are tubercle bacilli that cause a similar type of disease, but the primary hosts are fish, frogs, and turtles. Mycobacterium cheloni is frequently found in the soil and water, and in 1980 a microbiologist recognized this bacillus as a cause of lung disease, wound infections, and skin abscesses in humans (4, 22). In 1991, M. haemophilum surfaced as a pathogen when cases occurred in immunocompromised individuals in New York hospitals (4, 22).

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