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Scientists ID Two Receptor Families Used by Dengue Virus to Penetrate Cells

By demonstrating that it is possible to inhibit viral infection in vitro by blocking the bonding between the Dengue virus and TIM and TAM receptors, researchers have opened the way to a new antiviral strategy. Their work was published online in Cell Host & Microbe on 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 causes influenza-like 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 new therapeutic strategies be developed. Ali Amara's team at INSERM, together with colleagues, 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 two 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 and colleagues revealed that phosphatidylserine is abundantly expressed at the surface of virions and that it is 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. [Press release] [Cell Host & Microbe abstract]