Low density lipopolyprotein inhibits flavivirus acquisition in Aedes aegypti

Abstract

Aedes aegypti is the primary vector of a number of human pathogens including dengue virus (DENV) and Zika virus (ZIKV). Ae. aegypti acquires these viruses during the processing of bloodmeals obtained from an infected vertebrate host. Vertebrate blood contains a number of factors that have the potential to modify virus acquisition in the mosquito. Interestingly, low density lipopolyprotein (LDL) levels are decreased during severe DENV infection. Accordingly, we hypothesized that LDL is a modifiable factor that can influence flavivirus acquisition in the mosquito. We found that LDL is endocytosed by Ae. aegypti cells in a dynamin-dependent manner. LDL is also endocytosed by midgut epithelial cells and accumulates at the luminal midgut epithelium during bloodmeal digestion. Importantly, pretreatment with LDL, but not high density lipopolyprotein (HDL), significantly inhibited both DENV and ZIKV infection in vitro, and LDL inhibited ZIKV infection in vivo. This study identifies human LDL or 'bad cholesterol' as a modifiable factor that can inhibit flavivirus acquisition in Ae. aegypti. Identification of modifiable blood factors and critical cellular interactions that mediate pathogen acquisition may lead to novel strategies to disrupt the transmission cycle of vector-borne diseases.

Dengue virus reduces expression of low-density lipoprotein receptor-related protein 1 to facilitate replication in Aedes aegypti

“…Further, altering cholesterol distribution by modifying expression of sterol carrier protein 2 inhibited DENV infection 42 . Our laboratory found that human low-density lipoprotein inhibits flavivirus infection in vitro and in vivo 46 . It is clear that DENV is dependent on cholesterol itself or lipid sorting pathways in the mosquito.…”

“…aegypti is a cholesterol auxotroph; although, this lipid is readily available in each blood meal 48 . Aag2 cells and the midgut epithelium are able to take up human LDL via clathrin-mediated endocytosis 46 . Cholesterol uptake appears to benefit oogenesis, although our current data suggests that providing cell with lipid-depleted media only marginally reduces cell growth rate 48 .…”

Bovine Lactoferrin Inhibits Dengue Virus Infectivity by Interacting with Heparan Sulfate, Low-Density Lipoprotein Receptor, and DC-SIGN

“…LDLR is also a possible receptor for several viruses of the Flaviviridae family, such as hepatitis C virus (HCV) and JEV [ 6 , 29 ]. The amount of LDLR on the surface of Huh-7 cells was increased at the early stage of DENV infection [ 30 ], and LDL had showed an inhibition against DENV infection [ 31 ]. In the present study, DENV-2 infection was inhibited by chicken anti-LDLR antibody and rLDLR.…”

Arbovirus lifecycle in mosquito: acquisition, propagation and transmission

“…Indeed, LDL acquired from host blood can be endocytosed by the mosquito midgut epithelial cells and accumulate at the luminal epithelium during blood digestion, therefore hindering flavivirus acquisition in A. aegypti by blood meal (Ref. 15). In addition, a haemoglobin metabolite called haem can induce the expression of genes related to redox metabolism, thereby triggering large, variable expression of energy metabolism and immune genes in the mosquito gut to modulate the vectorial susceptibility to arboviruses (Ref.…”