TIM and TAM: 2 paths used by the Dengue virus to penetrate cells

October 23, 2012

By demonstrating that it is possible to inhibit the viral infection in vitro by blocking the bonding between the virus and these receptors, the researchers have opened the way to a new antiviral strategy. These works were published on line in the review "Cell Host & Microbe" of October 18, 2012.

The Dengue virus circulates in four different forms (four serotypes). It is transmitted to humans by mosquitoes. It is a major public health problem. Two billion people throughout the world are exposed to the risk of infection and 50 million cases of Dengue fever are recorded by the WHO every year. The infection is often asymptomatic, or resembles influenza symptoms, but its most serious forms can lead to fatal haemorrhagic fevers. At present, there is no preventive vaccine or efficient antiviral treatment for these four Dengue serotypes. So it is of vital importance that we develop new therapeutic strategies.

Ali Amara's team performed genetic screening in order to identify cell receptors used by the virus to penetrate target cells . The researchers have determined the important function played by the TIM receptors (TIM-1, 3, 4) and TAM receptors (AXL and TYRO-3) in the penetration process of the four Dengue serotypes. Mr. Amara's team has succeeded in demonstrating that the expression of these 2 receptor families makes cells easier to infect. In addition, the researchers observed that interfering RNA or antibodies that target the TIM and TAM molecules considerably reduced the infection of the cells targeted by the Dengue virus. The TIM and TAM molecules belong to two distinct families of transmembrane receptors that interact either directly (TIM) or indirectly (TAM) with phosphatidylserine, an "eat-me" signal that allows the phagocytosis and the elimination of these apoptopic cells. Unexpectedly, the work of the Inserm researchers discovered that phosphatidylserine is abundantly expressed at the surface of virions and that it was essential that the TIM and TAM receptors recognize the phosphatidylserine to allow infection of target cells.

These results have helped to understand the first key stage in the Dengue virus infectious cycle, by discovering a new method of virus entry that works by mimicking the biological functions involved in the elimination of the apoptotic cells. The discovery of these new receptors has also opened the way for new antiviral strategies aimed at blocking bonding of the Dengue virus with the TIM and TAM molecules.
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This research has been patent-protected by Inserrm Transfert.

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"The TIM and TAM Families of Phosphatidylserine Receptors Mediate Dengue Virus Entry" Laurent Meertens,1,2,3,6 Xavier Carnec,1,2,3,6 Manuel Perera Lecoin,1,2,3,6 Rasika Ramdasi,1,2,3 Florence Guivel-Benhassine,4 Erin Lew,5 Greg Lemke,5 Olivier Schwartz,4 and Ali Amara1,2,3,

1 Unité Inserm 944, Laboratoire de Pathologie et Virologie Moléculaire

2Institut Universitaire d'Hématologie Hôpital Saint-Louis, 1 Avenue Claude Vellefaux. 75010 Paris, France

3University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, 1 Avenue Claude Vellefaux, 75475 Paris, Cedex 10, France

4Unité Virus et Immunité , Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris, France

5Molecular Neurobiology Laboratory, Immunobiology and Microbial Pathogenesis Laboratory, The Salk Institute, La Jolla, CA 92037, USA

Cell Host and Microbe, 12, issue 4, October 18, 2012 http://www.sciencedirect.com/science/article/pii/S1931312812003046

INSERM (Institut national de la santé et de la recherche médicale)

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