Botulinum neurotoxins: more and more diverse and fascinating toxic proteins.

Botulism is a rare but severe disease mainly resulting from food poisoning or intestinal colonization. Food poisoning, including botulism, certainly occurred in ancient times. However, this disease was not recognized as a distinct pathological entity until the latter half of the 18th century. A first detailed description of the clinical symptoms was provided by Kerner in Germany (1815–1817), who investigated numerous cases in southwest Germany resulting from the consumption of blood sausage. The disease was called “sausage poisoning”. Notably, Kerner concluded that a toxin develops in blood sausage under anaerobic conditions that it is lethal at very small doses and induces flaccid paralysis. He speculated that this toxin may have a therapeutic application in suppressing muscle tonicity or hypersecretion of body fluids of neurological disorders manifesting by overactivity. In 1895, van Emmingen identified the causative agent, Bacillus botuliinum, later renamed Clostridium botulinum, which he isolated from a ham and from a human who died from botulism during a severe outbreak in Belgium. He found that the culture filtrates administrated to experimental animals induce the symptoms of botulism and lead to death. A few years later (1904), Landman isolated a strain from canned beans, which caused a German botulism outbreak. This was a unique event showing that botulism is a disease not only of meats or fish, but also of vegetables. Leuch (1910), from the Royal Institute of Infections in Berlin, found on the basis of the absence of cross-neutralization that the 2 strains produce distinct toxins. From the end of 18th century to the beginning of the 19th century, numerous cases have also been reported in the United States, mainly due to the consumption of heattreated canned vegetables, which was a novel mode of food preservation at that time. It appeared that the botulinum toxin (BoNT) produced by the American strains differed from that of the European strains. The strains from canned vegetables were designated type A, and those from ham were designated type B [1]. Strains isolated from chickens with botulism in the United States and cattle in Australia were identified as belonging to a novel type, termed type C by Bergston and Seddon (1922). A distinct microorganism was isolated from a bovine with botulism in South Africa by Meyer and Gunnison (1928) and was called type D. In 1934, 2 outbreaks of human botulism caused by the consumption of fish in New York and in the Ukraine were identified as type E by Gunnison et al (1936–1937), because the strains from both of these outbreaks were both antigenically similar and distinct from the previously identifiedC. botulinum strains. Type F was identified in Langeland, Denmark, in 1958 in specimens from 2 persons who had eaten a homemade liver paste, and C. botulinum type G was isolated in 1970 in specimens of soil in Argentina by Gimenez and Cicarelli [1]. Botulism was first recognized as a result of food poisoning. Other forms of botulism have been identified, such as wound botulism in 1940–1945, and botulism by intestinal colonization with neurotoxigenic strains in young infants (infant botulism) in 1976 [2] and later in adults [3]. Arnon and colleagues have investigated numerous cases of infant botulism, which is currently the prevalent form of botulism in the United States, and have developed a therapy based on human immune globulins [4, 5]. The taxonomic position of C. botulinum was originally based on 1 phenotype—the production of a BoNT—whereas the nontoxic variant strains were assigned to different species, such as Clostridium sporogenes and Clostridium subterminale. Subsequently, physiological differences Received and accepted 28 August 2013; electronically published 7 October 2013. Correspondence: Michel R. Popoff, DVM, PhD, Institut Pasteur, Bactéres Anaérobies et Toxines, 75714 Paris cedex15, France ([email protected]). The Journal of Infectious Diseases 2014;209:168–9 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit505