Diphtheria (corynebacterium Diphtheriae)
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Diphtheria (Corynebacterium diphtheriae)Corynebacteria are Gram-positive, aerobic, nonmotile, rod-shaped bacteriarelated to the Actinomycetes. They do not form spores or branch as do theactinomycetes, but they have the characteristic of forming irregular shaped, club-shaped or V-shaped arrangements in normal growth. They undergo snappingmovements just after cell division which brings them into characteristicarrangements resembling Chinese letters. The genus Corynebacterium consists of a diverse group of bacteria includinganimal and plant pathogens, as well as saprophytes. Some corynebacteria are partof the normal flora of humans, finding a suitable niche in virtually everyanatomic site. The best known and most widely studied species is Corynebacteriumdiphtheriae, the causal agent of the disease diphtheria. History and BackgroundNo bacterial disease of humans has been as successfully studied as diphtheria. The etiology, mode of transmission, pathogenic mechanism and molecular basis ofexotoxin structure, function, and action have been clearly established. Consequently, highly effective methods of treatment and prevention of diphtheriahave been developed. The study of Corynebacterium diphtheriae traces closely the development ofmedical microbiology, immunology and molecular biology. Many contributions tothese fields, as well as to our understanding of host-bacterial interactions, have been made studying diphtheria and the diphtheria toxin. Hippocrates provided the first clinical description of diphtheria in the 4thcentury B. C.
There are also references to the disease in ancient Syria and Egypt. In the
17th century, murderous epidemics of diphtheria swept Europe; in Spain'El garatillo' (the strangler'), in Italy and Sicily, 'the gullet disease'.In the 18th century, the disease reached the American colonies and reachedepidemic proportions in 1735. Often, whole families died of the disease in a fewweeks. The bacterium that caused diphtheria was first described by Klebs in 1883, andwas cultivated by Loeffler in 1884, who applied Koch's postulates and properlyidentified Corynebacterium diphtheriae as the agent of the disease. In 1884, Loeffler concluded that C. diphtheriae produced a soluble toxin, andthereby provided the first description of a bacterial exotoxin. In 1888, Roux and Yersin demonstrated the presence of the toxin in the cell-freeculture fluid of C. diphtheriae which, when injected into suitable lab animals, caused the systemic manifestation of diphtheria. Two years later, von Behring and Kitasato succeeded in immunizing guinea pigswith a heat-attenuated form of the toxin and demonstrated that the sera ofimmunized animals contained an antitoxin capable of protecting other susceptibleanimals against the disease. This modified toxin was suitable for immunizinganimals to obtain antitoxin but was found to cause severe local reactions inhumans and could not be used as a vaccine. In 1909, Theobald Smith, in the U. S., demonstrated that diphtheria toxinneutralized by antitoxin (forming a Toxin-Anti-Toxin complex, TAT) remainedimmunogenic and eliminated local reactions seen in the modified toxin. For someyears, beginning about 1910, TAT was used for active immunization againstdiphtheria
TAT had two undesirable characteristics as a vaccine. First, thetoxin used was highly toxic, and the quantity injected could result in a fataltoxemia unless the toxin was fully neutralized by antitoxin. Second, theantitoxin mixture was horse serum, the components of which tended to beallergenic and to sensitize individuals to the serum. In 1913, Schick designed a skin test as a means of determining susceptibility orimmunity to diphtheria in humans. Diphtheria toxin will cause an inflammatoryreaction when very small amounts are injected intracutaneously. The Schick Testinvolves injecting a very small dose of the toxin under the skin of the forearmand evaluating the injection site after 48 hours. A positive test (inflammatoryreaction) indicates susceptibility (nonimmunity).
A negative test (no reaction)indicates immunity (antibody neutralizes toxin).In 1929, Ramon demonstrated the conversion of diphtheria toxin to its nontoxic, but antigenic, equivalent (toxoid) by using formaldehyde. He provided humanitywith one of the safest and surest vaccines of all time-the diphtheria toxoid. In 1951, Freeman made the remarkable discovery that pathogenic (toxigenic)strains of C. diphtheriae are lysogenic, (i. e., are infected by a temperate Bphage), while non lysogenized strains are avirulent. Subsequently, it was shownthat the gene for toxin production is located on the DNA of the B phage. In the early 1960s, Pappenheimer and his group at Harvard conducted experimentson the mechanism of a action of the diphtheria toxin. They studied the effectsof the toxin in HeLa cell cultures and in cell-free systems, and concluded thatthe toxin inhibited protein synthesis by blocking the transfer of amino acidsfrom tRNA to the growing polypeptide chain on the ribosome. They found that thisaction of the toxin could be neutralized by prior treatment with diphtheriaantitoxin. Subsequently, the exact mechanism of action of the toxin was shown, and thetoxin has become a classic model of a bacterial exotoxin. Human DiseaseDiphtheria is a rapidly developing, acute, febrile infection which involves bothlocal and systemic pathology. A local lesion develops in the upper respiratorytract and involves necrotic injury to epithelial cells.
As a result of thisinjury, blood plasma leaks into the area and a fibrin network forms which isinterlaced with with rapidly-growing C. diphtheriae cells. This membranousnetwork covers over the site of the local lesion and is referred to as thepseudomembrane. The diphtheria bacilli do not tend to invade tissues below or away from thesurface epithelial cells at the site of the local lesion. At this site theyproduce the toxin that is absorbed and disseminated through lymph channels andblood to the susceptible tissues of the body. Degenerative changes in thesetissues, which include heart, muscle, peripheral nerves, adrenals, kidneys, liver and spleen, result in the systemic pathology of the disease. In parts of the world where diphtheria still occurs, it is primarily a diseaseof children, and most individuals who survive infancy and childhood haveacquired immunity to diphtheria. In earlier times, when nonimmune populations(i. e., Native Americans) were exposed to the disease, people of all ages wereinfected and killed. PathogenicityThe pathogenicity of Corynebacterium diphtheriae includes two distinctphenomena:1.Invasion of the local tissues of the throat, which requires colonizationand subsequent bacterial proliferation.
Nothing is known about the adherencemechanisms of this pathogen.2.Toxigenesis: bacterial production of the diphtheria toxin. The virulence ofC. diphtheriae cannot be attributed to toxigenicity alone, since a distinctinvasive phase apparently precedes toxigenesis. However, it cannot be ruled outthat the diphtheria toxin plays a (essential?) role in the colonization processdue to its short-range effects at the colonization site. Three strains of Corynebacterium diphtheriae are recognized, gravis, intermediusand mitis. They are listed here by falling order of the severity of the diseasethat they produce in humans. All strains produce the identical toxin and arecapable of colonizing the throat.
The differences in virulence between the threestrains can be explained by their differing abilities to produce the toxin inrate and quantity, and by their differing growth rates. The gravis strain has a generation time (in vitro) of 60 minutes; theintermedius strain has a generation time of about 100 minutes; and the mitisstain has a generation time of about 180 minutes. The faster growing strainstypically produce a larger colony on most growth media. In the throat (in vivo),a faster growth rate may allow...
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