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Rabies research at the Institut Pasteur

Today, rabies is considered a neglected disease: few laboratories in the world study it, while it remains a real problem for public health across the world. At the Institut Pasteur, where the rabies vaccine was developed by Louis Pasteur at the end of the 19thcentury (see p. 10), three research laboratories are currently devoted to studying the rabies virus and the fatal disease it causes. Much remains to be discovered: why doesn't the virus destroy the neurons it infects? How to find a treatment when it is too late to turn to vaccination? How to make an early diagnosis of the disease? And so on.

A virus that advances while hidden and pushes neurons to survive

The rabies virus is neurotropic; i.e. it infects the neurons. It spreads in the organism, from the muscle to the central nervous system, from neuron to neuron: therefore it is in the virus’ interest in having the cells carrying it survive. While the majority of viruses kill the cells they infect, the rabies virus has the distinctive characteristic of extending their survival. In the Institut Pasteur’s Neuro-Immuno Virology Laboratory, directed by Monique Lafon, the researchers seek to understand by what means the rabies virus keeps neurons alive. In other words, by studying the interaction between the rabies virus and a neuron, one can dissect the neuron’s survival mechanisms. Beyond the rabies problem, such research can have applications in fighting neurodegenerative diseases, where the question is precisely how to make neurons survive that are destroyed in the course of the disease. The same laboratory is also exploring the mechanisms that allow the rabies virus to evade the immune system: the researchers have discovered that the virus makes molecules on the surface of the neurons express in a way that masks it with respect to the organism’s defence cells.


Blocking the rabies virus

If one classically "treats" rabies by vaccination, this "treatment" is only effective when it is begun quickly after the infection and scrupulously continued until its completion. It involves several injections and visits to the doctor, which is comparatively intense, especially in developing countries; on the other hand, no therapeutic solution exists when the virus has reached the nervous system and the disease is overt. Hence the interest in researching antiviral molecules against the rabies virus, which would give rise to new treatments. This is one of the objectives of the Antiviral Strategies Unit, directed by Noël Tordo. Two approaches are used: a cognitive approach that aims to decipher the replication complex of the virus in order to identify therapeutic targets, and a random approach that consists of testing small molecules haphazardly and evaluating their inhibitory activity over the multiplication of the virus. Candidates with a strong antiviral effect have now been identified and are being studied.
Furthermore, the team is developing vaccines to control rabies in dogs-man’s best friend, but also the most favourable reservoir for transmission to humans. These are "extended spectrum" vaccines in order to be effective against the divergent lyssaviruses (of various origins) and can be administered orally, allowing stray dogs in developing countries to be reach.


From one lyssavirus to the next

Each species (fox, dog, bat, etc.) is infected by specific types of lyssaviruses, the viruses responsible for rabies. What is their evolutionary history? Why is the fox strain less pathogenic than the dog strain? The bat lyssaviruses seem to pass to humans with difficulty: could the situation change? There are many questions that the researchers are seeking to answer in the Lyssavirus Dynamics and Host Adaptation Unit (directed by Hervé Bourhy) through ecology/epidemiology studies and investigations of virulence and the host. They are also studying the matrix protein for the lyssaviruses, with the hope of someday being able to block it and give rise to new treatments. In addition, this unit is exploring the early, nonspecific responses of the infection-research that could lead to diagnosis, a domain in which the researchers have different leads.

Controlling rabies in North Africa

The European programme RABMEDCONTROL, coordinated jointly by the Instituts Pasteur of Paris and Tunis, has the goal of eliminating rabies in North Africa where it is still responsible for several hundred human deaths every year. It involves many research, public health, and veterinary institutions from three countries of southwestern Europe and four countries from North Africa. The laboratories concerned have started on a study of the disease within the endemic foci of North Africa in order to establish the different epidemiological and sociological reasons that explain why rabies persists in these countries despite all of the efforts that have been made. The programme also analyses the routes that allow the virus to reach the Mediterranean coasts of Europe, studying the impact of the illegal importation of infected domestic carnivores, especially dogs, and the bat species that live on the two shores of the Mediterranean and are able to serve as vectors and reservoirs for the virus. All of this data should eventually enable them to propose to health authorities effective strategies for eliminating this terrible disease in North Africa.