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Interferon-induced transmembrane proteins block Zika virus infection and prevent a non-apoptotic, paraptosis-like cell death pathway

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Air date: Wednesday, June 14, 2017, 4:15:00 PM
Time displayed is Eastern Time, Washington DC Local
Views: Total views: 100, (42 Live, 58 On-demand)
Category: Immunology
Runtime: 00:53:42
Description: Immunology Interest Group Seminar Series

The clinical outcome of viral infection, the difference between survival and death of the host, rests delicately on events occurring at the molecular level of individual cells. The ‘cell-intrinsic’ arm of innate immunity prevents virus replication by detecting virus invasion and interfering with the viral life cycle. As such, cell-intrinsic immune factors, also known as host restriction factors, impose the earliest acting barriers to invading pathogens. Innate immunity controls Zika virus (ZIKV) infection and disease in most infected patients through mechanisms that remain to be understood. Furthermore, the cytopathic effects of ZIKV are widely discussed but poorly described. Here, we studied the morphological cellular changes induced by ZIKV and addressed the role of interferon-induced transmembrane proteins (IFITM), a family of broad spectrum antiviral factors, during viral replication. We report that ZIKV induces massive vacuolization followed by “implosive” cell death in human epithelial cells, primary skin fibroblasts and astrocytes, a phenomenon which is exacerbated when IFITM3 levels are low. It is reminiscent of paraptosis, a caspase-independent, non-apoptotic form of cell death associated with the formation of large cytoplasmic vacuoles. We further show that ZIKV-induced vacuoles are derived from the endoplasmic reticulum (ER) and dependent on the PI3K/Akt signaling axis. Inhibiting the Sec61 ER translocon in ZIKV-infected cells blocked vacuole formation and viral production. Our results provide mechanistic insight behind the ZIKV-induced cytopathic effect and indicate that IFITM3, by acting as a gatekeeper for incoming virus, restricts virus takeover of the ER and subsequent cell death. Future directions include determining whether additional antiviral functions of IFITM3, such as the reduction of HIV-1 virion fusogenicity, also manifest during flavivirus infections.

Alex Compton received his Ph.D. in Molecular and Cellular Biology from the University of Washington in 2012. As a doctoral student in the laboratory of Dr. Michael Emerman (Fred Hutchinson Cancer Research Center), he investigated the HIV-1 Vif protein and its target APOBEC3G, revealing lentivirus-driven evolution of host proteins on a million-year time scale. Dr. Compton was the recipient of a Pasteur Foundation Postdoctoral Fellowship and an ANRS (French National Agency on AIDS Research) Grant during his postdoctoral training with Dr. Olivier Schwartz at the Pasteur Institute in Paris, where he made key discoveries on the mechanisms by which the interferon-induced transmembrane (IFITM) proteins restrict HIV-1 infection. These studies provide important insight into the complex ways in which mammalian cells have evolved to counteract viral infections. In 2017, Dr. Compton joined the HIV Dynamics and Replication Program as Head of the Antiviral Immunity and Resistance Section to develop a research program focused on mechanisms of protection mediated by the cell-intrinsic innate immune response, as well as the strategies employed by HIV and emerging viruses to evade or overcome these immune barriers.
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NLM Title: Interferon-induced transmembrane proteins block zika virus infection and prevent a non-apoptotic, paraptosis-like cell death pathway / Alex Compton.
Author: Compton, Alex A.
National Institutes of Health (U.S.),
Publisher:
Abstract: (CIT): The clinical outcome of viral infection, the difference between survival and death of the host, rests delicately on events occurring at the molecular level of individual cells. The "cell-intrinsic" arm of innate immunity prevents virus replication by detecting virus invasion and interfering with the viral life cycle. As such, cell-intrinsic immune factors, also known as host restriction factors, impose the earliest acting barriers to invading pathogens. Innate immunity controls Zika virus (ZIKV) infection and disease in most infected patients through mechanisms that remain to be understood. Furthermore, the cytopathic effects of ZIKV are widely discussed but poorly described. Here, we studied the morphological cellular changes induced by ZIKV and addressed the role of interferon-induced transmembrane proteins (IFITM), a family of broad spectrum antiviral factors, during viral replication. We report that ZIKV induces massive vacuolization followed by "implosive" cell death in human epithelial cells, primary skin fibroblasts and astrocytes, a phenomenon which is exacerbated when IFITM3 levels are low. It is reminiscent of paraptosis, a caspase-independent, non-apoptotic form of cell death associated with the formation of large cytoplasmic vacuoles. We further show that ZIKV-induced vacuoles are derived from the endoplasmic reticulum (ER) and dependent on the PI3K/Akt signaling axis. Inhibiting the Sec61 ER translocon in ZIKV-infected cells blocked vacuole formation and viral production. Our results provide mechanistic insight behind the ZIKV-induced cytopathic effect and indicate that IFITM3, by acting as a gatekeeper for incoming virus, restricts virus takeover of the ER and subsequent cell death. Future directions include determining whether additional antiviral functions of IFITM3, such as the reduction of HIV-1 virion fusogenicity, also manifest during flavivirus infections.
Subjects: Interferon Inducers--immunology
Protein Transport--immunology
Viral Proteins--metabolism
Zika Virus Infection--immunology
Publication Types: Lectures
Webcasts
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NLM Classification: WC 524
NLM ID: 101708397
CIT Live ID: 18600
Permanent link: https://videocast.nih.gov/launch.asp?23357