Host cell factors in filovirus entry: novel players, new insights

Abstract

Filoviruses cause severe hemorrhagic fever in humans with high case-fatality rates. The cellular factors exploited by filoviruses for their spread constitute potential targets for intervention, but are incompletely defined. The viral glycoprotein (GP) mediates filovirus entry into host cells. Recent studies revealed important insights into the host cell molecules engaged by GP for cellular entry. The binding of GP to cellular lectins was found to concentrate virions onto susceptible cells and might contribute to the early and sustained infection of macrophages and dendritic cells, important viral targets. Tyrosine kinase receptors were shown to promote macropinocytic uptake of filoviruses into a subset of susceptible cells without binding to GP, while interactions between GP and human T cell Ig mucin 1 (TIM-1) might contribute to filovirus infection of mucosal epithelial cells. Moreover, GP engagement of the cholesterol transporter Niemann-Pick C1 was demonstrated to be essential for GP-mediated fusion of the viral envelope with a host cell membrane. Finally, mutagenic and structural analyses defined GP domains which interact with these host cell factors. Here, we will review the recent progress in elucidating the molecular interactions underlying filovirus entry and discuss their implications for our understanding of the viral cell tropism.

Figure 1

Domain organization of selected viral class I membrane fusion proteins. Viral class I membrane fusion proteins contain an N-terminal surface unit, which binds to cellular receptors, and a C-terminal transmembrane unit, which harbors the membrane fusion machinery. The glycoproteins are synthesized as inactive precursor proteins, which are primed for membrane fusion by proteolytic processing at the border between both subunits (the activating cleavage site is indicated by an arrow). For Ebola virus (EBOV)- viral glycoprotein (GP₀), the receptor binding region (RBR) is shown. The C-terminal membrane fusion subunits of the respective glycoproteins, which anchor the proteins in the viral membranes, contain the following characteristic architectural elements required for membrane fusion: heptad repeats and a hydrophobic fusion peptide. The figure is adapted from [44,54].

Figure 2

Host cell surface proteins involved in filovirus uptake. Cellular lectins bind glycans present on the filoviral GP_1,2 and thereby promote attachment to target cells. The surface molecule TIM-1 interacts with GP_1,2 inserted in the viral membrane. TAM proteins do not bind to GP_1,2 but elicit signals which promote viral uptake by macropinocytosis. Integrins might interact with GP_1,2 and are important for intracellular processing of GP_1,2.

Figure 3

Infectious entry of filoviruses into target cells. After interaction between GP_1,2 and cellular surface molecules, virions are internalized via macropinocytosis into the endosomal compartment. Subsequently, the endosomal cysteine proteases cathepsin B and L proteolytically process GP_1,2 , thereby removing the glycan cap (indicated by grey caps) and allowing primed GP₁ binding to Niemann-Pick C1 (NPC1), which is essential for the following virus-host membrane fusion process. Finally, a so far incompletely understood stimulus triggers the membrane fusion activity in GP₂.