Bacterial neurotoxins today and tomorrow
Director of the Laboratoire Neurotransmission et sécrétion neuroendocrine (Neuroendocrine Secretion and Neurotransmission Laboratory, CNRS),
Clostridium botulinum neurotoxins, the tetanus toxin, the toxin of the anthrax bacillus, the diphtheria toxin, the lethal Clostridium sordellii toxin… These are some of the most powerful toxins known to us. These names arouse concern because of their potential use as biological weapons. An attempt was made to use the botulism toxin during the Gulf War (cf. the Iraqi projects from 1985 to 1990). It was probably used by the Aum Shinririkyo sect in Japan in 1995. As for the anthrax bacillus, we all remember the fall of 2001 in the United States. As a neurobiologist, I will restrict my talk to an overview of the bacterial toxins that affect operation of the nervous system, while emphasizing more particularly what has been achieved by the French teams.
Bacterial neurotoxins are all produced by anaerobic bacteria of the Clostridium type. Tetanus is due to the presence of a toxin produced by C. tetani in abscesses. Very good protection of populations has been obtained by mass vaccination. Thus, in Europe, the occurrence of tetanus is now only 0.5 cases per year for 1 million inhabitants, whereas, in the third world, where vaccination is not yet systematic, there are about 0.5 fatal cases per year for 10,000 inhabitants.
Botulism neurotoxins have a paralyzing action. Through progress in food safety, botulism has become a rare disease (about 30 cases of botulism per year in France). Botulism toxins have been used clinically for over ten years now as a palliative treatment for certain motor disorders (focal dystonia, spasticity). It can be estimated that one French person in every 10,000 is concerned by such use. In the United States and in Great Britain, the use of botulism toxins in esthetic indications is a fact of society and represents an annual market of over 500 million euros. Other applications, such as oral vaccines, based on derivatives from botulism toxins, are emerging in the USA. Those vaccines make use of the fact that botulism neurotoxins cross the intestinal wall before being disseminated into the organism.
The tetanus toxin is captured by the motor neurons and then transported towards the central nervous system. This property has been used experimentally to send proteins linked to non-toxic fragments of the tetanus toxin specifically to the neurons. Unfortunately, therapeutic use of the derivatives of the tetanus toxin remains impossible because we are all vaccinated.
This illustrates the dilemma that would be posed by mass botulism vaccination to protect people from the potential use of botulism toxins as biological weapons. How can we protect ourselves from them without jeopardizing their numerous biomedical applications? A first possibility is seroneutralization of the circulating toxin via antibodies or fragments of antibodies. Between the beginning of a toxinosis and the effective application of a seroneutralization, the botulism toxins have had time to be captured by the neurons. One of the avenues being explored to halt their intraneuronal action concerns the capture of neutralizing antibody fragments by the neurons. In 1992, the discovery showing that Clostridium neurotoxins are proteases paved the way for synthesizing powerful inhibitors that are very specific to these toxins. The problem of these inhibitors crossing the plasma membranes of the neurons has not yet been fully solved.
Do other bacterial neurotoxins exist that might be used to act on the nervous system? Recent work conducted on the Clostridium difficile B toxin, and the Clostridium sordellii LT toxin show us that they do. C. difficile is involved in severe enteritis (inflammations of the intestinal mucus) occurring in particular after antibiotherapy. It is the most frequent nosocomial disease (an estimated 3 million cases per year in the United States). In humans, C. sordellii is involved in rare cases of hemorrhagic enteritis, gangrene, and myonecrosis. When they are applied to neurons, the C. sordellii LT toxin and the C. difficile B toxin have an action blocking the release of transmitters, comparable to the action of the botulism toxin and of the tetanus toxin. These observations give a rational basis for explaining the origin of the neurological disorders noted when poisoning is caused by these toxins. Now, the question is whether other bacterial toxins can lie behind new biological dangers.
Director of the Laboratoire Neurotransmission et sécrétion neuroendocrine (CNRS), Strasbourg
Tel: +33 3 88 45 66 77