Cholesterol Transporters NPC1 and NPC2 as Entry Inhibitors Against Filovirus Infection

Cholesterol transporters NPC1 and NPC2 form an essential trafficking pathway to transport cholesterol molecules from late endosomes/lysosomes to cytoplasm. However, filoviruses, such as Ebola virus and Marburg virus, hijack the intracellular cholesterol transporter 1 (also called Niemann-Pick C1 protein, NPC1) as the receptor to infect cells in the late endosomes/lysosomes. Intriguingly, the filovirus binding site overlaps with NPC2 on the NPC1 that is located at loops 1 and 2 of NPC1_C domain. It is suggested that the NPC2 and filovirus directly compete for binding to NPC1 for their functions. In this study, we utilize this competing relationship to counteract filovirus infection directly using NPC1 and NPC2 proteins. The soluble NPC1_C domain is used as a fake receptor for absorbing filovirus particles, and NPC2 is used to interfere with filovirus binding to NPC1 for entry. The outcomes from our studies have shown that both cholesterol proteins indeed exhibit strong activities against filovirus infection. It is feasible that these cholesterol transporter proteins could be developed as therapeutics to treat filovirus infection.