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 characteristic sterile haemorrhagic 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 the tox structural gene was carried by a bacteriophage (Uchida, Gill & Pappenhcimer, 1971).