Late Endosomal/Lysosomal Cholesterol Accumulation Is a Host Cell-Protective Mechanism Inhibiting Endosomal Escape of Influenza A Virus
ABSTRACT To transfer the viral genome into the host cell cytoplasm, internalized influenza A virus (IAV) particles depend on the fusion of the IAV envelope with host endosomal membranes. The antiviral host interferon (IFN) response includes the upregulation of interferon-induced transmembrane protei...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2018-09-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01345-18 |
| _version_ | 1819199665780817920 |
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| author | Alexander Kühnl Agnes Musiol Nicole Heitzig Danielle E. Johnson Christina Ehrhardt Thomas Grewal Volker Gerke Stephan Ludwig Ursula Rescher |
| author_facet | Alexander Kühnl Agnes Musiol Nicole Heitzig Danielle E. Johnson Christina Ehrhardt Thomas Grewal Volker Gerke Stephan Ludwig Ursula Rescher |
| author_sort | Alexander Kühnl |
| collection | DOAJ |
| description | ABSTRACT To transfer the viral genome into the host cell cytoplasm, internalized influenza A virus (IAV) particles depend on the fusion of the IAV envelope with host endosomal membranes. The antiviral host interferon (IFN) response includes the upregulation of interferon-induced transmembrane protein 3 (IFITM3), which inhibits the release of the viral content into the cytosol. Although IFITM3 induction occurs concomitantly with late endosomal/lysosomal (LE/L) cholesterol accumulation, the functional significance of this process is not well understood. Here we report that LE/L cholesterol accumulation itself plays a pivotal role in the early antiviral defense. We demonstrate that inducing LE/L cholesterol accumulation is antiviral in non-IFN-primed cells, restricting incoming IAV particles and impairing mixing of IAV/endosomal membrane lipids. Our results establish a protective function of LE/L cholesterol accumulation and suggest endosomal cholesterol balance as a possible antiviral target. IMPORTANCE With annual epidemics occurring in all parts of the world and the risk of global outbreaks, influenza A virus (IAV) infections remain a major threat to public health. Infected host cells detect viral components and mount an interferon (IFN)-mediated response to restrict virus propagation and spread of infection. Identification of cellular factors and underlying mechanisms that establish such an antiviral state can provide novel strategies for the development of antiviral drugs. The contribution of LE/L cholesterol levels, especially in the context of the IFN-induced antiviral response, has remained controversial so far. Here, we report that accumulation of cholesterol in the LE/L compartment contributes to the IFN-induced host cell defense against incoming IAV. Our results establish cholesterol accumulation in LE/L per se as a novel antiviral barrier and suggest the endosomal cholesterol balance as a putative druggable host cell factor in IAV infection. |
| first_indexed | 2024-12-23T03:19:57Z |
| format | Article |
| id | doaj.art-6c3d712588c4446f9847a58b5227d3c0 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-23T03:19:57Z |
| publishDate | 2018-09-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-6c3d712588c4446f9847a58b5227d3c02022-12-21T18:02:01ZengAmerican Society for MicrobiologymBio2150-75112018-09-019410.1128/mBio.01345-18Late Endosomal/Lysosomal Cholesterol Accumulation Is a Host Cell-Protective Mechanism Inhibiting Endosomal Escape of Influenza A VirusAlexander Kühnl0Agnes Musiol1Nicole Heitzig2Danielle E. Johnson3Christina Ehrhardt4Thomas Grewal5Volker Gerke6Stephan Ludwig7Ursula Rescher8Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, Muenster, GermanyInstitute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, Muenster, GermanyInstitute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, Muenster, GermanyProgram in Cell Biology, Hospital for Sick Children, Toronto, Ontario, CanadaInstitute of Virology, Center for Molecular Biology of Inflammation, University of Muenster, Muenster, GermanyFaculty of Pharmacy A15, University of Sydney, Sydney, NSW, AustraliaInstitute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, Muenster, GermanyInstitute of Virology, Center for Molecular Biology of Inflammation, University of Muenster, Muenster, GermanyInstitute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, Muenster, GermanyABSTRACT To transfer the viral genome into the host cell cytoplasm, internalized influenza A virus (IAV) particles depend on the fusion of the IAV envelope with host endosomal membranes. The antiviral host interferon (IFN) response includes the upregulation of interferon-induced transmembrane protein 3 (IFITM3), which inhibits the release of the viral content into the cytosol. Although IFITM3 induction occurs concomitantly with late endosomal/lysosomal (LE/L) cholesterol accumulation, the functional significance of this process is not well understood. Here we report that LE/L cholesterol accumulation itself plays a pivotal role in the early antiviral defense. We demonstrate that inducing LE/L cholesterol accumulation is antiviral in non-IFN-primed cells, restricting incoming IAV particles and impairing mixing of IAV/endosomal membrane lipids. Our results establish a protective function of LE/L cholesterol accumulation and suggest endosomal cholesterol balance as a possible antiviral target. IMPORTANCE With annual epidemics occurring in all parts of the world and the risk of global outbreaks, influenza A virus (IAV) infections remain a major threat to public health. Infected host cells detect viral components and mount an interferon (IFN)-mediated response to restrict virus propagation and spread of infection. Identification of cellular factors and underlying mechanisms that establish such an antiviral state can provide novel strategies for the development of antiviral drugs. The contribution of LE/L cholesterol levels, especially in the context of the IFN-induced antiviral response, has remained controversial so far. Here, we report that accumulation of cholesterol in the LE/L compartment contributes to the IFN-induced host cell defense against incoming IAV. Our results establish cholesterol accumulation in LE/L per se as a novel antiviral barrier and suggest the endosomal cholesterol balance as a putative druggable host cell factor in IAV infection.https://journals.asm.org/doi/10.1128/mBio.01345-18IFITM3influenza A virusannexin A6interferonlate endosomal cholesterol content |
| spellingShingle | Alexander Kühnl Agnes Musiol Nicole Heitzig Danielle E. Johnson Christina Ehrhardt Thomas Grewal Volker Gerke Stephan Ludwig Ursula Rescher Late Endosomal/Lysosomal Cholesterol Accumulation Is a Host Cell-Protective Mechanism Inhibiting Endosomal Escape of Influenza A Virus mBio IFITM3 influenza A virus annexin A6 interferon late endosomal cholesterol content |
| title | Late Endosomal/Lysosomal Cholesterol Accumulation Is a Host Cell-Protective Mechanism Inhibiting Endosomal Escape of Influenza A Virus |
| title_full | Late Endosomal/Lysosomal Cholesterol Accumulation Is a Host Cell-Protective Mechanism Inhibiting Endosomal Escape of Influenza A Virus |
| title_fullStr | Late Endosomal/Lysosomal Cholesterol Accumulation Is a Host Cell-Protective Mechanism Inhibiting Endosomal Escape of Influenza A Virus |
| title_full_unstemmed | Late Endosomal/Lysosomal Cholesterol Accumulation Is a Host Cell-Protective Mechanism Inhibiting Endosomal Escape of Influenza A Virus |
| title_short | Late Endosomal/Lysosomal Cholesterol Accumulation Is a Host Cell-Protective Mechanism Inhibiting Endosomal Escape of Influenza A Virus |
| title_sort | late endosomal lysosomal cholesterol accumulation is a host cell protective mechanism inhibiting endosomal escape of influenza a virus |
| topic | IFITM3 influenza A virus annexin A6 interferon late endosomal cholesterol content |
| url | https://journals.asm.org/doi/10.1128/mBio.01345-18 |
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