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The antibody dependent enhancement (ADE) of dengue virus infection in U937 cells requires cholesterol rich membrane microdomains

¹ Centro de Investigacion y Estudios Avanzados-IPN;
² Instituto Venezolano de Investigaciones Científicas

³ E-mail: rmangel{at}cinvestav.mx

Dengue virus is the causative agent of dengue fever and the more severe forms of the infection known as dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Secondary infections with a serotype different from the primary infection are considered a risk factor for the development of DHF/DSS. One explanation for the increased risk of DHF/DSS development after heterologous secondary infections is the antibody dependent enhancement (ADE) hypothesis. This hypothesis postulates that pre-existing non-neutralizing antibodies will form immune complexes with the new serotype-infecting virus that in turn, will have enhanced capacity to infect macrophages and other Fc receptor (FcvR) bearing cells. Despite the evidence supporting the ADE hypothesis, the molecular mechanisms of ADE are not fully understood. In this work, we present evidence which indicates that intact lipid rafts are required for the ADE infection of U937 cells with dengue virus. Flow cytometry analysis to measure percentage of infected cells, showed that treatment of differentiated U937 cells with nystatin (30µg/ml), filipin (10µg/ml) or β-methyl cyclodextrin (30mM) reduces significantly (p< 0.05) the ADE of dengue 4 virus infection in vitro without any effect in viability and in the number of FcvR bearing cells. Later cholesterol replenishment by supplementing treated cell cultures with bovine fetal serum for 24 hrs, reestablished lipid raft integrity and reversed the alteration of the ADE in vitro (p< 0.05). Our results suggest that ADE of U937 infection by dengue virus requires the presence of cholesterol and cholesterol rich membrane microdomains.

Received 27 July 2009; accepted 11 October 2009.