The dengue virus non-structural protein 1 (NS1) use the scavenger receptor B1 as cell receptor in human hepatic and mosquito cells

Abstract

Dengue is the most common virus disease transmitted to humans by mosquitoes. The dengue virus NS1 is a multifunctional protein that form part of replication complexes. In addition, NS1 is also secreted, as a hexamer, to the extracellular milieu. Circulating NS1 has been associated with dengue pathogenesis by several different mechanisms. Cell binding and internalization of soluble NS1 result in the disruption of tight junctions and in down regulation of the innate immune response. In this work, we report that the HDL scavenger receptor B1 (SRB1) in human hepatic cells, and a scavenger receptor B1-like in mosquito C6/36 cells act as cell surface binding receptor for dengue virus NS1. The presence of the SRB1 on the plasma membrane of C6/36 cells, as well as in Huh-7 cells, was demonstrated by confocal microcopy. Internalization of NS1 can be efficiently blocked by anti-SRB1 antibodies and previous incubation of the cells with HDL significantly reduces NS1 internalization. In addition, the transient expression of SRB1 in Vero cells, which lack the receptor, renders these cells susceptible to NS1 entry. Direct interaction between soluble NS1 and the SRB1 in Huh7 and C6/36 cells was demonstrated in vivo by proximity ligation assays an in vitro by surface plasmon resonance. Finally, data is presented indicating that the SRB1 also act as cell receptor for zika virus NS1. These results demonstrate that dengue virus NS1, a bona fide lipoprotein, usurps the HDL receptor for cell entry and offers explanations for the altered serum lipoprotein homeostasis observed in dengue patients.