Niemann-pick C1 is essential for ebolavirus replication and pathogenesis in vivo

Andrew S. Herbert, Cristin Davidson, Ana I. Kuehne, Russell Bakken, Stephen Z. Braigen, Kathryn E. Gunn, Sean P. Whelan, Thijn R. Brummelkamp, Nancy A. Twenhafel, Kartik Chandran, Steven U. Walkley, John M. Dye

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Recent work demonstrated that the Niemann-Pick C1 (NPC1) protein is an essential entry receptor for filoviruses. While previous studies focused on filovirus entry requirements of NPC1 in vitro, its roles in filovirus replication and pathogenesis in vivo remain unclear. Here, we evaluated the importance of NPC1, and its partner in cholesterol transport, NPC2, by using a mouse model of Ebolavirus (EBOV) disease. We found that, whereas wild-type mice had high viral loads and succumbed to EBOV infection, Npc1−/− mice were entirely free of viral replication and completely protected from EBOV disease. Interestingly, Npc1+/− mice transiently developed high levels of viremia, but were nevertheless substantially protected from EBOV challenge. We also found Npc2−/− mice to be fully susceptible to EBOV infection, while Npc1−/− mice treated to deplete stored lysosomal cholesterol remained completely resistant to EBOV infection. These results provide mechanistic evidence that NPC1 is directly required for EBOV infection in vivo, with little or no role for NPC1/NPC2-dependent cholesterol transport. Finally, we assessed the in vivo antiviral efficacies of three compounds known to inhibit NPC1 function or NPC1-glycoprotein binding in vitro. Two compounds reduced viral titers in vivo and provided a modest, albeit not statistically significant, degree of protection. Taken together, our results show that NPC1 is critical for replication and pathogenesis in animals and is a bona fide target for development of antifilovirus therapeutics. Additionally, our findings with Npc1+/− mice raise the possibility that individuals heterozygous for NPC1 may have a survival advantage in the face of EBOV infection.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalmBio
Volume6
Issue number3
DOIs
StatePublished - May 26 2015

    Fingerprint

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Herbert, A. S., Davidson, C., Kuehne, A. I., Bakken, R., Braigen, S. Z., Gunn, K. E., Whelan, S. P., Brummelkamp, T. R., Twenhafel, N. A., Chandran, K., Walkley, S. U., & Dye, J. M. (2015). Niemann-pick C1 is essential for ebolavirus replication and pathogenesis in vivo. mBio, 6(3), 1-12. https://doi.org/10.1128/mBio.00565-15