Ebola virus entry requires the cholesterol transporter Niemann-Pick C1

Carette J., et al. 2011. Nature 477, 340-343

Speaker: Yu-Chi Su (蘇育琦)                                        Time: 15:10~16:00, Dec. 21, 2011

Commentator: Dr. Chih-Li Hsu (胥直利老師)             Place: Room 601

Abstract:

Infection by the Ebola and Marburg filoviruses causes sever haemorrhagic fever with mortality rates over 75% and still lack of antiviral therapeutics or vaccines. Filoviruses use viral spike glycoprotein (GP) to enter host endosome, which contains host factors are required for viral andendosomal membrane fusion. In this paper, to identify those unknown host factors, the authors use a genome-wide haploid genetic screen in HAP1 cells. They discovered two endosomal-associated proteins, including homotypic fusion and vacuole protein-sorting (HOPS) complex, which affects the fusion of endosomes to lysosomes, and Niemann-Pick C1 (NPC1), which is responsible for the endosomal membrane cholesterol transport. They found that cells lost of HOPS complex or NPC1 function are resistant to Ebola and Marburg virus infection, but still susceptible to other unrelated viruses. To further clarify NPC1 is required for filovirus-GP-mediated infection, they tested primary fibroblast from Niemann-Pick type C1 disease patients who lack NPC1 hereditarily. They showed that NPC1-null cells or drugs targeting to NPC1 can resist to viral infection. In HOPS complex or NPC1 defective cells, the viral/endosomal fusion and uncoating are both arrested. This suggests that NPC1 protein is not only required for filovirus and endosomal membrane fusion, but also crucial for viral release from the endo/lysosomal vesicular compartment. Most importantly, NPC1^+/- mice are resistant to Ebola and Marburg virus-caused mice death. The unanticipated role of NPC1 in viral infection pathway may facilitate the development of antifilovirus therapeutics and vaccines.

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