Dengue: we are not all equal in the eyes of this disease

Dengue, a virosis which is raging in tropical areas, is transmitted by mosquitoes. It affects 100 million people each year throughout the world. The genetic analysis of a large cohort of subjects who were hospitalised with this disease in Thailand has enabled researchers at the Institut Pasteur, together with researchers from Inserm (the National Institute for Health and Medical Research), to highlight the role of a genetic variant in individuals afflicted by severe forms of dengue. This research, which was published in Nature Genetics, demonstrates the importance of the DC-SIGN molecule, a co-receptor of the dengue virus, in the pathogenesis of this disease. These results bring new insight to the current hypotheses on disease mechanisms in severe forms of dengue, and may have important consequences for the development of preventive and therapeutic strategies against this disease. The newly identified genetic variant could also be involved in the susceptibility to other infections in which the DC-SIGN molecule plays a part.

 

 

Press release
Paris, april 25, 2005

 

 

Are there some genetic factors which predispose people to the risk of infection through the dengue virus or the development of serious forms of the disease?

To answer this question, the Cécile Julier team, which is responsible for the Institut Pasteur-Inserm Joint Unit "Genetics of Infectious and Autoimmune Diseases, (Institut Pasteur, Inserm Unit 730), analysed the genetic profile of a cohort of 600 patients who were hospitalised in Thailand for dengue and near 700 control individuals. This research was undertaken in partnership with Mahidol University in Bangkok, the National Genotyping Centre in Evry and the Flavivirus-Hosts Interactions Unit of the Institut Pasteur.

The research focused on a particular gene, coding for DC-SIGN, a molecule which had been identified in 2003 at the Institut Pasteur* as a co-receptor that is essential for infecting target human cells with the dengue virus.

It is recognized that most dengue virus infections (approximately 90%) are asymptomatic, or result in undifferentiated fever. Amongst patients suffering from severe forms of dengue fever, two clinical forms have been defined - dengue fever (DF) and dengue haemorrhagic fever (DHF); the latter, which is extremelysevere and may result in death, is clinically distinguished from the former by the presence of plasma leakage.

Initially, molecular screening of the gene coding for DC-SIGN was performed, in order to identify all its genetic variants. Researchers then showed that one of these variants was associated with strong protection against DF: amongst the patients hospitalised for this disease, those who were carriers of this variant had 5 times less chance of developing DF than non carriers, although this variant has no effect on the risk of developing the most sever form, DHF. This research shows that these two severe forms of the disease involve pathophysiological mechanisms which are at least in partly distinct .

Functional research carried out by researchers on this DC-SIGN variant suggests that its protective role may be due to a decrease in the amount DC-SIGN co-receptor on the surface of the dengue virus target cells (dendritic cells). The lack of protection against DHF associated with this phenomenon leads us to believe that in this form of the disease other mechanisms short-circuit or reduce the importance of the role of the DC-SIGN co-receptor.

These conclusions strengthens the idea that DC-SIGN is a key molecule in the research for dengue therapies, and its differential role in the two clinical forms has to be considered from now on.The genetic differences which have now been highlighted between individuals should be taken into account in the future trials for prevention (e.g. vaccine tests) or therapy based on this molecule.

This gene does not explain all inter-individual differences in the response to dengue virus infection, and Cécile Julier’s team and her colleagues are continuing their research into other genes are involved in the risk of infection or the severity of the diseasein infected people.

These results may have implications on research involving pathologies other than dengue. In addition to its major role in arboviruses infections (dengue, West Nile virus fever, yellow fever and Japanese encephalitis), DC-SIGN is also an attachment molecule for various other infectious agents that are of major interest to public health: HIV, hepatitis C virus, cytomegalovirus, Ebola virus, SARS virus, tuberculosis bacillus and certain parasites. So, the variant which has just been identified may be involved in the genetic susceptibility to wide range of infectious diseases.

Sources

"A variant in the CD209 promoter is associated with the severity of dengue disease", Nature Genetics, May 2005
Anavaj Sakuntabhai (1, 2), Chairat Turbpaiboon (1, 3), Isabelle Casadémont (1), Ampaiwan Chuansumrit (4), Tassanee Lowhnoo (1, 5, 6), Anna Kajaste-Rudnitski (7), Sita Mint Kalayanarooj (1, 8), Kanchana Tangnararatchakit (4), Nattaya Tangthawornchaikul (9), Sirijit Vasanawathana (10), Wathanee Chaiyaratana (6), Pa-thai Yenchitsomanus (8, 9), Prapat Suriyaphol (8), Panisadee Avirutnan (8), Kulkanya Chokephaibulkit (11), Fumihiko Matsuda (5), Sutee Yoksan (12), Yves Jacob (13), G Mark Lathrop (5), Prida Malasit (8, 9), Philippe Desprès (7) and Cécile Julier (1)

1 Genetics of Infectious and Auto-immune Diseases, Institut Pasteur, Inserm E102, 28 rue du docteur Roux, 75724 Paris Cedex 15, France.
2 Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI, Bangkok 10400, Thailand.
3 Department of Biochemistry, Faculty of Science, Ramathibodi Hospital, Mahidol University, Rama VI, Bangkok 10400, Thailand.
4 Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI, Bangkok 10400, Thailand.
5 National. Genotyping Centre, 2 rue Gaston Crémieux, CP 5721, 91057 Evry Cedex, France.
6 Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI, Bangkok 10400, Thailand.
7 Flavivirus-Hosts Molecular Interactions , Institut Pasteur, 25 rue du docteur Roux, 75724 Paris cedex 15, France.
8 Medical Molecular Biology Unit, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok 10700, Thailand.
9 Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology BIOTEC, National Science and Technology Development Agency NSTDA, Pathumthani 12120, Thailand.
10 Department of Pediatrics, Khon Kaen Hospital, Ministry of Public Health, Khonkaen 40000, Thailand.
11 Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700 Thailand.
12 Center for Vaccine Development, Institute of Science and Technology for Research and Development, Mahidol University, 25/25 Moo 3, Phuttamonthon 4 Road, Salaya, Phuttamonthon District, Nakhon Pathom 73170, Thailand.
ethics, Papillomavirus and Human Cancer, Institut Pasteur, 25 rue du docteur Roux, 75724 Paris Cedex 15, France.

* "Dengue: a virus receptor indentified", press release of 8 July 2003:

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