Press release

DISCOVERY OF A GENE LEADING TO SENSITIVITY TO
THE WEST NILE VIRUS

The infection caused by the West Nile virus, transmitted to humans by mosquitoes and which is currently rife in the United States, is generally harmless or even has no visible symptoms in the majority of those infected while, in others, it may trigger fatal encephalitis. Could the genetic makeup of the individuals explain these differences in sensitivity to the infection? That is what researchers from the Pasteur Institute are suggesting having highlighted a gene in mice which is a possible candidate for sensitivity to this "emerging" virus. This gene may also explain the individual sensitivities to viruses from the same family, also responsible for fatal diseases in a certain number of those infected: dengue hemorrhagic fever, yellow fever, Japanese encephalitis etc. This work, to be published in PNAS (Proceedings of National Academy of Sciences), opens up promising prospects for the perfection of diagnostic tests, treatments and even vaccines to fight viruses that are spreading more and more, along with the mosquitoes that transmit them.

Having recently emerged in the United States (New York, 1999), currently responsible for more than a hundred cases of human infection and several deaths in various American states, the West Nile virus is present throughout various regions worldwide. Discovered in 1937 in Uganda (hence its name), it has since been isolated in Africa, the Middle East, India and Europe where an outbreak in 1996-97 in Romania affected some 500 persons, resulting in death in 10% of cases. In France, although the last human cases go back to the sixties, an epidemic among horses in Camargue bore witness to the presence of the virus within our country in late 2000.
Infection with the West Nile infection is characterised by the appearance of a high fever accompanied by headache and backache, muscular pains, a cough, swelling of the lymph glands, and often a skin rash, abdominal pains and respiratory symptoms. Complications occur in less than 15% of cases: encephalitis, hepatitis, pancreatitis or myocarditis. In general, the patient recovers spontaneously, sometimes with after-effects, but the disease may prove fatal, particularly in fragile subjects (the elderly and young children). Beyond this age-related fragility, are there other factors explaining the differing degrees of severity observed in response to this infection?

The results of a study involving several teams from the Pasteur Institute (Programme Transversal de Recherche (Cross Research Program) combining the Mammals' Genetics Unit1, the Flavivirus Hosts Molecular Interactions Unit2, the Rabies Unit and the Biology of Emerging Viral Infections Unit), headed by Jean-Louis Guénet1 and Philippe Desprès2, come in support of this hypothesis. In effect, the researchers have highlighted a gene candidate for sensitivity to this infection in a West Nile viral infection murine model. This corroborates the results of an American team which recently put forward this gene as a possible candidate for sensitivity to the flavivirus in general. Let us reiterate that flaviviruses, all transmitted by mosquitoes, include, in addition to the West Nile virus, the Dengue fever virus (responsible for 60 to 100 million infections each year worldwide and 20,000 deaths a year, and against which there exists no treatment or vaccine), that of yellow fever (still, in spite of the existence of an effective vaccine, responsible for some 200,000 cases and 30,000 deaths a year within the African continent alone) or even that of Japanese encephalitis, extremely common in South East Asia and also generating a high mortality rate.
Those flavivirus infections considered to be emerging or re-emerging are therefore real and growing public health problems against which there is no treatment nor, except in the case of yellow fever, vaccine. The anti-mosquito fight, difficult to implement for both practical, economic and scientific reasons (growing resistance of certain species of mosquito to insecticides), today remains the only way of countering the majority of these infections. And, at the same time, the mosquitoes - and therefore the viruses carried by them - are spreading more and more easily thanks to international transport or climatic conditions (global warming).

The gene highlighted by researchers therefore opens up interesting prospects for research. On the one hand, it is first and foremost a matter of checking that what has been discovered in mice can be transposed to humans. At the Pasteur Institute, Cécile Julier's laboratory (Unit representing the Genetics of Auto-immune and Infectious Diseases) is leading the investigations in this direction, carrying out research within human cohorts to determine whether the variations in the gene corresponding to the gene candidate found in mice are associated with severe forms of Dengue fever (Dengue haemorrhagic). Such studies may ultimately result in the perfection of tests enabling the severity of infection with a flavivirus to be predicted in a given individual.

At the same time, other teams from the Pasteur Institute are devoting their time to studying the antiviral response mechanisms associated with the gene candidate, for which it is known that they affect the innate defences of the host. By this means, it is hoped that it will be possible to find treatments or vaccinations against these infections, or even more than that: the mechanisms being researched in effect seem dependent on the alpha interferon, the body's natural antiviral mechanism used today in the treatment of infections such as hepatitis C, also caused by a virus from the West Nile virus family.

The gene revealed by scientists therefore opens the way for studies which it is hoped will end, in the medium term, in effective methods of combating flavivirus infections.

Source:

"A nonsense mutation in the gene encoding 2'-5'-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice": PNAS, Aug. 2002. Tomoji Mashimo*, Marianne Lucas¤, Dominique Simon-Chazottes*, Marie-Pascale Frenkiel¤, Xavier Montagutelli*, Pierre-Emmanuel Ceccaldi#, Vincent Deubel§, Jean-Louis Guenet* and Philippe Despres¤ :

* Unité de Génétique des mammifères (Genetics of Mammals Unit), Institut Pasteur, Paris, France
¤ Unité des Interactions Moléculaires Flavivirus-Hôtes (Flavivirus Host Molecular Interactions Unit), Institut Pasteur, Paris, France
# Unité de la rage (Rabies Unit), Institut Pasteur, Paris, France
§ Unité de Biologie des Infections Virales Emergentes (Biology of Emerging Viral Infections Unit), Institut Pasteur, Lyon, France

Contacts :

- Jean-Louis Guénet - Tel: +33(0) 145 688 555 - E-mail : guenet@pasteur.fr
- Philippe Desprès - Tel: +33(0) 140 613 563 - E-mail : pdespres@pasteur.fr
- Press Office, Institut Pasteur - Tel: +33(0) 145 688 146 - Fax: +33(0) 140 613 030 - Email: presse@pasteur.fr