Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12202/360
Title: Filovirus requirements and susceptibility: Niemann-pick Cl is a genetic determinant of Ebola virus infection in bats
Authors: Ng, Melinda
Keywords: Virology.
Molecular biology.
Evolution & development.
Issue Date: 2015
Publisher: ProQuest Dissertations & Theses
Citation: Source: Dissertation Abstracts International, Volume: 77-07(E), Section: B.;Advisors: Kartik Chandran.
Abstract: Lloviu virus (LLOV), a phylogenetically divergent filovirus, is the proposed etiologic agent of Schreibers's long-fingered bat (Miniopterus schreibersii ) die-offs in western Europe. Studies of LLOV remain limited because the infectious agent has not yet been isolated. Here, we generated a recombinant vesicular stomatitis virus expressing the LLOV spike glycoprotein (GP) and used it to show that LLOV GP resembles other filovirus GP proteins in structure and function. LLOV GP must be cleaved by endosomal cysteine proteases during entry, but is much more protease-sensitive than EBOV GP. The EBOV/MARV receptor, Niemann--Pick Cl (NPC1), is also required for LLOV entry, and its second luminal domain is recognized with high affinity by a cleaved form of LLOV GP, suggesting that receptor binding would not impose a barrier to LLOV infection of humans and non-human primates. The use of NPC1 as an intracellular entry receptor may be a universal property of filoviruses.;Additionally, we explored the role of NPC 1 in contributing to species-specific patterns of filovirus infection in African pteropodid bats. While Ebola virus (EBOV) can infect a broad host range, little is known about the biological factors that influence susceptibility. We identified that cells derived from the African straw-colored fruit bat (Eidolon helvum) are resistant to EBOV infection, while cells from sympatric bat species are fully susceptible. The resistance in African straw-colored fruit bat cells can be explained by a single amino acid change in the endogenous NPC1, which greatly reduces the EBOV-NPC1 interaction. Genetic analysis suggests that NPC1 is under positive selection at the exact residue that controls EBOV infection in these cells. These findings identify NPC1 as the first known genetic determinant of filovirus susceptibility in bats, and suggest that the polymorphism in the African straw-colored fruit bat NPC 1 may reflect a host adaptation to control replication of EBOV. We also identified a single mutation in EBOV GP that increases EBOV-NPC1 affinity in E. helvum, revealing a possible avenue for a co-evolutionary arms race between the host and virus.
URI: https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:10014272
https://hdl.handle.net/20.500.12202/360
Appears in Collections:Albert Einstein College of Medicine: Doctoral Dissertations

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