Entry of Ebolavirus (EBOV) into host cells is mediated by its sole glycoprotein, known as GP. The GP and its associated EBOV entry events possess many unusual features that provide novel insights into our fundamental understanding of viral entry. In this R21 project, we aim to elucidate how the newly identified cellular restricton factors, known as interferon-inducible transmembrane (IFITM) proteins, especially IFITM2, potently and specifically inhibit EBOV entry, and in doing so, aid the development of novel antiviral therapeutics.
Aim 1 : Establish a single virus fusion assay for EBOV and dissect the stages of membrane fusion inhibited by IFITM2. We will take advantage of the fact that EBOV GP can be efficiently incorporated into its virus-like particles (VLPs) formed by the VP40 matrix protein, and develop a single virus imaging and fusion system to determine how IFITM2 inhibits EBOV fusion in endolysosomes.
Aim 2 : Elucidate the molecular and biochemical mechanisms by which IFITM2 specifically inhibits EBOV GP-mediated entry. We will test the central hypothesis that IFITM2 profoundly inhibits EBOV entry by disturbing the triggering capability and/or the cholesterol transport activity of its intracellular receptor, Niemann-Pick C1 (NPC1). A series of biochemical and novel fluorescence lipid labeling techniques will be used to assess the effect of IFITM2 on cholesterol content, membrane fluidity, and conformational changes of EBOV GP. EBOV is a highly pathogenic filovirus that causes severe hemorrhagic fever in humans, with a fatality rate of up to 90%. Results from the proposed studies will provide critical novel insight into how IFITM2 restricts EBOV GP-mediated membrane fusion and entry, as well as advance our understanding of the general mechanism of IFITMs that block viral entry.
Ebola virus causes fatal hemorrhagic fever in human and non-human primates. Currently, no effective drug or FDA-approved vaccine is available for this deadly virus. This project will study how some cellular factors intrinsically inhibit Ebola virus entry into host cells, which may lead to new strategies to prevent and treat infection by Ebola.
|Li, Anzhong; Yu, Jingyou; Lu, Mijia et al. (2018) A Zika virus vaccine expressing premembrane-envelope-NS1 polyprotein. Nat Commun 9:3067|
|Wang, Tongtong; Du, Qian; Wu, Xingchen et al. (2018) Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation. J Virol 92:|
|Du, Qian; Wu, Xingchen; Wang, Tongtong et al. (2018) Porcine Circovirus Type 2 Suppresses IL-12p40 Induction via Capsid/gC1qR-Mediated MicroRNAs and Signalings. J Immunol 201:533-547|
|Yu, Jingyou; Liang, Chen; Liu, Shan-Lu (2017) Interferon-inducible LY6E Protein Promotes HIV-1 Infection. J Biol Chem 292:4674-4685|
|Miller, A Dusty; De Las Heras, Marcelo; Yu, Jingyou et al. (2017) Evidence against a role for jaagsiekte sheep retrovirus in human lung cancer. Retrovirology 14:3|
|Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min et al. (2016) Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger. PLoS Pathog 12:e1005373|
|Miao, Chunhui; Li, Minghua; Zheng, Yi-Min et al. (2016) Cell-cell contact promotes Ebola virus GP-mediated infection. Virology 488:202-15|
|Qian, Jin; Le Duff, Yann; Wang, Yimeng et al. (2015) Primate lentiviruses are differentially inhibited by interferon-induced transmembrane proteins. Virology 474:10-8|
|Jia, Rui; Ding, Shilei; Pan, Qinghua et al. (2015) The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity. PLoS One 10:e0118794|
|Yu, Jingyou; Li, Minghua; Wilkins, Jordan et al. (2015) IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein. Cell Rep 13:145-156|
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