The diphtheria bacillus and its toxin: a model system

Abstract

Friedrich Loeffler's classical paper entitled ‘Untersuchungen über die Bedeutung der Mikroorganismen für die Entstehung der Diphtheric beim Menschen, bei der Taube und der Kalbe’ (Studies on the significance of bacteria in causing diphtheria in man, pigeons and calves), was published in 1884. In this paper and those which followed during the next few years, Loeffler described the diphtheria bacillus and its isolation in pure culture, and proved its relationship to the disease diphtheria. While the credit for the discovery of diphtheria toxin must go to Roux & Yersin (1888), Loeffler clearly predicted its existence in his original paper. Because, at autopsy, living ‘virulent’ diphtheria bacilli could only be recovered from experimental animals at the site of injection, Loeffler postulated that the bacteria must have released into the bloodstream a ‘chemical poison’ which caused the characteristicsterilehaemorrhagic lesions in remote organs. He even noted early in 1888 that ‘the bacterial poison resembles in its action the poison [now known as abrin] obtained from jaquiriti seeds, which causes inflammation and the production of false membranes when placed on the mucous membranes either of men or animals’ (cited in Loeffler, 1908). Today we know the reason for this astute observation. Both abrin and diphtheria toxin block protein synthesis in sensitive eucaryotic cells (Collier, 1975; Olsnes & Pihl, 1976; Pappenheimer, 1977), albeit by different mechanisms. Almost a quarter of a century after the discovery of the diphtheria bacillus, the British Medical Research Council published a 718-page volume on diphtheria. In the first chapter Loeffler (1908) reviewed the history of the disease and reminisced at some length about his own early work. By 1908 when this book appeared, a good deal was already known about the epidemiology of diphtheria, the bacteriology of the diphtheria bacillus, its mode of spread by healthy adults and the protective effect of antitoxin. However, other than its proteinaceous nature almost nothing was known of the chemistry of diphtheria toxin or its mode of action. The interpretation of many of Loeffler's astute early observations and questions that puzzled him remained obscure and unanswerable until the discovery of lysogenic conversion to toxinogenicity by Freeman (1951) and the realization that thetoxstructural gene was carried by a bacteriophage (Uchida, Gill & Pappenhcimer, 1971).

Adhesion by Pathogenic Corynebacteria

“…Bretonneau also made the astonishing association of the organism releasing a "blood poison," similar to that found in jequirity seeds (Pappenheimer, 1984). This diphtheria-associated toxin was eventually isolated by Emile Roux and Alexander Yersin (Roux and Yersin, 1888), soon after Friedrich Loeffler demonstrated the etiological agent of diphtheria by growing it in pure culture (Kwantes, 1984;Loeffler, 1884).…”

Nucleotide sequence of the Shiga-like toxin genes of Escherichia coli.

“…Several observations suggest this homology is significant: (i) Shiga toxin and ricin share similar mechanisms of toxic activity on eukaryotic cells; (ii) the similarity score for the comparison between SltA and ricin A was the highest observed in the entire data base, using a variety of search parameters and techniques; this similarity score was well within the range generally considered to have biological significance (29); and (iii) the predictions of secondary structure by the algorithm of Chou-Fasman were virtually identical in the area of highest homology between the two peptides. The possibility that prokaryotic toxins are evolutionarily related to eukaryotic enzymes has been suggested before in relation to diphtheria toxin (38,39) and cholera toxin (40). We now present evidence for this hypothesis by demonstrating amino acid sequence homology between the A subunits of a prokaryotic (SLT) and a eukaryotic toxin (ricin).…”

Phage Conversion and the Role of Bacteriophage and Host Functions in Regulation of Diphtheria Toxin Production by Corynebacterium diphtheriae

“…The N-terminal domain of DT is the proenzyme form of the catalytically active fragment A that mediates intracellular intoxication; the centrally positioned translocation domain (T-domain) mediates entry of the fragment A into the cytosol of the target cell; and the C-terminal receptor-binding domain (R-domain) mediates binding of DT to its cell-surface receptor Gill and Pappenheimer 1971;Gill and Dinius 1971;Drazin et al 1971). Early studies showed that DT is highly toxic for humans and some other animals such as rabbits and guinea pigs, and the minimal lethal dose of DT for humans and other highly susceptible animals is approximately 0.1 μg/kg of body weight (Pappenheimer 1984). Some animal species including mice and rats are much more resistant to the toxic effects of DT.…”