Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones
The threat of viral pandemics demands a comprehensive understanding of evolution at the host–pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that t...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020
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| Online Access: | https://hdl.handle.net/1721.1/125570 |
| _version_ | 1826189631462309888 |
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| author | Phillips, Angela Marie Ponomarenko, Anna Butty, Vincent L G Whittaker, Charles A. Moore, Christopher Lawrence Shoulders, Matthew D. Chen, Kenny,Ph. D.Massachusetts Institute of Technology. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Phillips, Angela Marie Ponomarenko, Anna Butty, Vincent L G Whittaker, Charles A. Moore, Christopher Lawrence Shoulders, Matthew D. Chen, Kenny,Ph. D.Massachusetts Institute of Technology. |
| author_sort | Phillips, Angela Marie |
| collection | MIT |
| description | The threat of viral pandemics demands a comprehensive understanding of evolution at the host–pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition–mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development. |
| first_indexed | 2024-09-23T08:18:41Z |
| format | Article |
| id | mit-1721.1/125570 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:18:41Z |
| publishDate | 2020 |
| publisher | Public Library of Science (PLoS) |
| record_format | dspace |
| spelling | mit-1721.1/1255702022-09-23T12:13:50Z Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones Phillips, Angela Marie Ponomarenko, Anna Butty, Vincent L G Whittaker, Charles A. Moore, Christopher Lawrence Shoulders, Matthew D. Chen, Kenny,Ph. D.Massachusetts Institute of Technology. Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT The threat of viral pandemics demands a comprehensive understanding of evolution at the host–pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition–mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development. 2020-05-29T12:42:47Z 2020-05-29T12:42:47Z 2018-09 2020-01-14T12:54:53Z Article http://purl.org/eprint/type/JournalArticle 1544-9173 https://hdl.handle.net/1721.1/125570 Phillips, Angela M. et al. “Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones.” PLoS biology 16 (2018): e3000008 © 2018 The Author(s) en https://dx.doi.org/10.1371/JOURNAL.PBIO.3000008 PLoS biology Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science (PLoS) PLoS |
| spellingShingle | Phillips, Angela Marie Ponomarenko, Anna Butty, Vincent L G Whittaker, Charles A. Moore, Christopher Lawrence Shoulders, Matthew D. Chen, Kenny,Ph. D.Massachusetts Institute of Technology. Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones |
| title | Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones |
| title_full | Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones |
| title_fullStr | Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones |
| title_full_unstemmed | Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones |
| title_short | Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones |
| title_sort | destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones |
| url | https://hdl.handle.net/1721.1/125570 |
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