Filovirus Tropism: Cellular Molecules for Viral Entry

Takada, Ayato

Recently, a bioinformatics approach, comparative genetics analysis, was used to screen the candidate genes involved in ZEBOV entry and T-cell immunoglobulin and mucin domain 1 (TIM-1) was identified as a candidate ZEBOV and MARV cellular receptor by correlation analysis between the gene expression profiles and permissiveness to viral infection (Kondratowicz et al., 2011) . TIM-1 was shown to bind to the RBR of ZEBOV GP, and ectopic TIM-1 expression in poorly permissive cells enhanced EBOV infection. In addition, reduction of cell-surface expression of TIM-1 by RNAi decreased infection of highly permissive Vero cells, which are commonly used for filovirus propagation. However, the fact that not all cell types that are naturally permissive for filoviruses express the above-mentioned molecules implies that filoviruses may utilize multiple cellular proteins for infection of a wide variety of cells. More recent studies suggest that endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1) is essential for filovirus infection, providing a model of EBOV infection in which cleavage of the GP1 subunit by endosomal cathepsin removes heavily glycosylated regions to expose the putative RBR, which is a ligand for NPC1 and mediates membrane fusion by the GP2 subunit (Carette et al., 2011; Côté et al., 2011) . Available data indicate that the cellular tropism of filoviruses does not necessarily match the distribution of any cellular molecules so far identified. Importantly, it remains elusive whether these molecules act as functional receptors that mediate both viral attachment and membrane fusion or as so-called co-receptors whose interaction with viral GP is required only for membrane fusion.