|
Dengue virus therapy targets host receptor Researchers from Taiwan found that blocking CLEC5A, one of the host receptors recognized by dengue virus, dampens the damaging inflammatory response that can result from infection. The study, which proposes a new treatment method for preventing tissue damage and improving the outcome of patients suffering from dengue hemorrhagic fever and dengue shock syndrome, appears in the May 29, 2008 issue of Nature. Dengue virus infects about 50 million people worldwide each year. Dengue hemorrhagic fever and dengue shock syndrome are distinguished from dengue fever, a less serious affliction, by the release of a storm of molecules, known as cytokines, that send the host immune system into a frenzy. Nobody knows exactly why, but it seems the onslaught is perpetrated by out-of-control macrophages, a type of immune cell that usually help fight infection. CLEC5A is a member of the C-type lectin family, a large group of glycan-binding proteins that vary widely in carbohydrate ligand and function, but share similarities in their carbohydrate recognition domains. CLEC5A also acts as a pattern recognition receptor - in this case recognizing fucose on the dengue viral surface. Interaction with other host receptors can stimulate dengue virus infection and replication, but this study revealed that viral interaction with CLEC5A triggers only cell signaling. In particular, signaling through this molecule stimulates macrophage secretion of TNF-alpha and other cytokines that stimulate the inflammatory responses that can lead to life-threatening complications. This study also demonstrated that treatment with an antibody directed against CLEC5A inhibits CLEC5A-dengue virus interaction and prevents the hemorrhaging and plasma leakage typically associated with the more serious forms of dengue virus infection. In a mouse model of disease, anti-CLEC5A antibody therapy resulted in a nearly 50% increase in survival rate three weeks after infection with the virus. The authors of this study began their relationship with the CFG by working with the Protein-Glycan Interaction Core (H) to screen a glycan array for ligands of a variety of C-type ligands. Now, after showing that CLEC5A interacts with viral particles and plays a role in viral-mediated inflammatory reaction, the authors have teamed up with the CFG Mouse Transgenics Core (F) to generate CLEC5A knockout mice in order to shed more light on the role CLEC5A plays during infection with dengue virus and other pathogens. Isolation of primary embryonic stem cells is currently underway and Core F expects to have the conditional knockout strain available in October 2008. Heather Buschman
Original Paper: Chen ST, Lin YL, Huang MT, Wu MF, Cheng SC, Lei HY, Lee CK, Chiou TW, Wong CH, Hsieh SL. CLEC5A is critical for dengue-virus-induced lethal disease. Nature. 2008 May 29;453(7195):672-6. |