Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats

Abstract

Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filovirus host range in nature.DOI: http://dx.doi.org/10.7554/eLife.11785.001

Comparative Transcriptomics Highlights the Role of the Activator Protein 1 Transcription Factor in the Host Response to Ebolavirus

“…During the course of this study, Ng and coworkers published the results of a study, which, like our data, showed that cells from E. helvum were largely refractory to infection by EBOV (42). Their study went on to show that the reduced permissiveness of these cells was caused by a mutation in the EBOV entry receptor, Niemann-Pick C1 (NPC1).…”

Neglected filoviruses

“…With the exception of genomic sequence determination and functional deductions one can possibly make from alignment with other ebolavirus sequences, only three reports have been published addressing BDBV molecular biology directly. BDBV uses Niemann-Pick C1 (NPC1) as a cellentry receptor (Ng et al 2015); cell entry is dependent on cathepsin B in vitro (Misasi et al 2012); and BDBV -peptide has no effect on MARV replication (Radoshitzky et al 2011). The pathology of human BDBV infection remains unknown as neither autopsies nor biopsies were performed during the two disease outbreaks.…”

“…These studies relied on recombinantly expressed LLOV proteins (Maruyama et al 2014;Feagins and Basler 2015) or on virus surrogate systems such as vesiculoviral pseudotypes (Maruyama et al 2014), retroviral pseudotypes (Ng et al 2014) or recombinant vesiculoviruses (Ng et al 2014(Ng et al , 2015 to study parts of the presumed LLOV replication cycle. Results indicate that the LLOV surface GP 1,2 mediates LLOV cell entry by binding to the universal endosomal filovirus receptor NPC1 (Ng et al 2014(Ng et al , 2015 in a pH-, cathepsin L-dependent (not cathepsin B-dependent) manner reminiscent of EBOV (Maruyama et al 2014;Ng et al 2014). As shown for other filoviruses, coexpression of LLOV GP 1,2 and matrix protein VP40 results in the formation of filamentous filovirion-like particles (Maruyama et al 2014).…”

“…Just like EBOV, RESTV suppresses the type I interferon response through VP35 and VP24, and the type II interferon response through VP24 (Kash et al 2006;Zhang et al 2012). RESTV uses NPC1 for cell entry (Ng et al 2015) and is dependent on cathepsin B (but not cathepsin L) for cell entry in vitro (Misasi et al 2012). Akin to LLOV, RESTVpeptide has little effect on MARV replication (Radoshitzky et al 2011).…”

“…Consequently, results from only a single study on a candidate vaccine for the prevention of TAFV are ambiguous (Table 7), and no TAFV-specific antivirals have been brought forward. Molecular-biological studies on TAFV are close to absent with the exception of the determination of the crystal structure of the TAFV NP C-terminal domain (Baker et al 2016) and the characterization of TAFV GP 1,2 -mediated cell-entry (NPC1 and cathepsin B) requirements (Misasi et al 2012;Ng et al 2015). Minigenomes and reverse genetics systems have yet to be established for TAFV.…”