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

eLife digest

Ebola virus and other filoviruses can cause devastating diseases in humans and other apes. Numerous small outbreaks of Ebola virus disease have occurred in Africa over the past 40 years. However, in 2013–2015, the largest outbreak on record took place in three Western African nations with no previous history of the disease.

Human outbreaks of Ebola virus disease likely begin when a person encounters an infected wild animal. Though it remains unclear precisely which animals harbor Ebola virus between outbreaks, and how they transmit the virus to humans or other primates, recent work showed that some filoviruses do infect specific types of bats in nature.

Ng, Ndungo, Kaczmarek et al. sought to identify the genes that influence whether or not a type of bat is susceptible to infection by Ebola virus and other filoviruses. Several filoviruses, including Ebola virus, were tested to see if they could infect cells that had been collected from four types of African fruit bats. These bats are all found in areas where outbreaks have occurred in the past.

The tests revealed that a small change in the sequence of the NPC1 gene in some bat cells greatly reduced their susceptibility to Ebola virus. NPC1 encodes a protein that mammals need in order to move cholesterol within their cells. In humans, the loss of the protein encoded by NPC1 causes a rare but very severe disease called Niemann-Pick type C disease. This protein also turns out to be a receptor that the filoviruses must bind to before they can infect the cells. Further analysis then revealed that NPC1 has evolved rapidly in bats, with changes concentrated in the parts of the receptor that interact with Ebola virus.

Ng, Ndungo, Kaczmarek et al. went on to discover some changes in the genome sequence of Ebola virus that could compensate for the changes in the bat’s NPC1 gene. These findings hint at one way that a filovirus could evolve to better infect a host with receptors that were less than optimal.

Following on from this work, the next challenges will be to expand the investigation to include additional types of bats, other types of mammals, and other host genes that could influence filovirus infection and disease. Further studies could also examine the other side of the arms race – that is, the evolution of viral genes in bats. However, such studies would be complicated by the lack of viral sequences that have been collected from bats, because to date most have been isolated from humans and other primates instead.

DOI: http://dx.doi.org/10.7554/eLife.11785.002