Maladaptation after a virus host switch leads to increased activation of the pro-inflammatory NF-κB pathway
SignificanceMyxoma virus (MYXV) is benign in the natural brush rabbit host but causes a fatal disease in European rabbits. Here, we demonstrate that MYXV M156 inhibited brush rabbit protein kinase R (bPKR) more efficiently than European rabbit PKR (ePKR). Because ePKR was not completely inhibited by...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2022-05, Vol.119 (20), p.e2115354119-e2115354119 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Yu, Huibin Peng, Chen Zhang, Chi Stoian, Ana M M Tazi, Loubna Brennan, Greg Rothenburg, Stefan |
| description | SignificanceMyxoma virus (MYXV) is benign in the natural brush rabbit host but causes a fatal disease in European rabbits. Here, we demonstrate that MYXV M156 inhibited brush rabbit protein kinase R (bPKR) more efficiently than European rabbit PKR (ePKR). Because ePKR was not completely inhibited by M156, there was a depletion of short-half-life proteins like the nuclear factor kappa B (NF-κB) inhibitor IκBα, concomitant NF-κB activation and NF-κB target protein expression in ePKR-expressing cells. NF-κB pathway activation was blocked by either hypoactive or hyperactive M156 mutants. This demonstrates that maladaptation of viral immune antagonists can result in substantially different immune responses in aberrant hosts. These different host responses may contribute to altered viral dissemination and may influence viral pathogenesis. |
| doi_str_mv | 10.1073/pnas.2115354119 |
| format | Article |
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Here, we demonstrate that MYXV M156 inhibited brush rabbit protein kinase R (bPKR) more efficiently than European rabbit PKR (ePKR). Because ePKR was not completely inhibited by M156, there was a depletion of short-half-life proteins like the nuclear factor kappa B (NF-κB) inhibitor IκBα, concomitant NF-κB activation and NF-κB target protein expression in ePKR-expressing cells. NF-κB pathway activation was blocked by either hypoactive or hyperactive M156 mutants. This demonstrates that maladaptation of viral immune antagonists can result in substantially different immune responses in aberrant hosts. These different host responses may contribute to altered viral dissemination and may influence viral pathogenesis.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2115354119</identifier><identifier>PMID: 35549551</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Crosstalk ; Depletion ; eIF-2 kinase ; eIF-2 Kinase - metabolism ; Host-Pathogen Interactions ; Inflammation ; Inhibition ; Interleukin 6 ; Kinases ; Metabolic Networks and Pathways ; Molecular modelling ; Mutants ; Myxoma ; Myxoma virus - genetics ; Myxoma virus - pathogenicity ; Myxomatosis ; Myxomatosis, Infectious - metabolism ; Myxomatosis, Infectious - virology ; NF-kappa B - metabolism ; NF-KappaB Inhibitor alpha - metabolism ; NF-κB protein ; Protein kinase R ; Proteins ; Rabbits ; Rabbits - virology ; Signal transduction ; Transfection ; Tumor necrosis factor-α ; Virulence ; Viruses</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2022-05, Vol.119 (20), p.e2115354119-e2115354119</ispartof><rights>Copyright National Academy of Sciences May 17, 2022</rights><rights>Copyright © 2022 the Author(s). Published by PNAS. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-3ff1dea5f890e4d357bd9f3c344d1d56442875df5374cff5e8794f29b45915193</citedby><cites>FETCH-LOGICAL-c421t-3ff1dea5f890e4d357bd9f3c344d1d56442875df5374cff5e8794f29b45915193</cites><orcidid>0000-0002-4339-9045 ; 0000-0003-2494-6901 ; 0000-0002-2430-272X ; 0000-0002-6687-7134 ; 0000-0002-2525-8230</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171774/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171774/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35549551$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Huibin</creatorcontrib><creatorcontrib>Peng, Chen</creatorcontrib><creatorcontrib>Zhang, Chi</creatorcontrib><creatorcontrib>Stoian, Ana M M</creatorcontrib><creatorcontrib>Tazi, Loubna</creatorcontrib><creatorcontrib>Brennan, Greg</creatorcontrib><creatorcontrib>Rothenburg, Stefan</creatorcontrib><title>Maladaptation after a virus host switch leads to increased activation of the pro-inflammatory NF-κB pathway</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>SignificanceMyxoma virus (MYXV) is benign in the natural brush rabbit host but causes a fatal disease in European rabbits. Here, we demonstrate that MYXV M156 inhibited brush rabbit protein kinase R (bPKR) more efficiently than European rabbit PKR (ePKR). Because ePKR was not completely inhibited by M156, there was a depletion of short-half-life proteins like the nuclear factor kappa B (NF-κB) inhibitor IκBα, concomitant NF-κB activation and NF-κB target protein expression in ePKR-expressing cells. NF-κB pathway activation was blocked by either hypoactive or hyperactive M156 mutants. This demonstrates that maladaptation of viral immune antagonists can result in substantially different immune responses in aberrant hosts. These different host responses may contribute to altered viral dissemination and may influence viral pathogenesis.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Crosstalk</subject><subject>Depletion</subject><subject>eIF-2 kinase</subject><subject>eIF-2 Kinase - metabolism</subject><subject>Host-Pathogen Interactions</subject><subject>Inflammation</subject><subject>Inhibition</subject><subject>Interleukin 6</subject><subject>Kinases</subject><subject>Metabolic Networks and Pathways</subject><subject>Molecular modelling</subject><subject>Mutants</subject><subject>Myxoma</subject><subject>Myxoma virus - genetics</subject><subject>Myxoma virus - pathogenicity</subject><subject>Myxomatosis</subject><subject>Myxomatosis, Infectious - metabolism</subject><subject>Myxomatosis, Infectious - virology</subject><subject>NF-kappa B - metabolism</subject><subject>NF-KappaB Inhibitor alpha - metabolism</subject><subject>NF-κB protein</subject><subject>Protein kinase R</subject><subject>Proteins</subject><subject>Rabbits</subject><subject>Rabbits - virology</subject><subject>Signal transduction</subject><subject>Transfection</subject><subject>Tumor necrosis factor-α</subject><subject>Virulence</subject><subject>Viruses</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1v1DAQhi0EotuWMzdkiQuXtJ7YXscXJFrRgtSWCz1bs7FNXCVxsJ2t9q_xI_hNpNpSPk5zmOd9NaOHkNfAToApfjqNmE9qAMmlANDPyAqYhmotNHtOVozVqmpELQ7IYc53jDEtG_aSHHAphZYSVqS_xh4tTgVLiCNFX1yiSLchzZl2MRea70NpO9o7tJmWSMPYJofZWYptCdt9LnpaOkenFKsw-h6HAUtMO3pzUf38cUYnLN097o7JC499dq8e5xG5vfj49fxTdfXl8vP5h6uqFTWUinsP1qH0jWZOWC7VxmrPWy6EBSvXQtSNktZLrkTrvXSN0sLXeiOkBgmaH5H3-95p3gzOtm4sCXszpTBg2pmIwfy7GUNnvsWt0aBAKbEUvHssSPH77HIxQ8it63scXZyzqddroRqtGF_Qt_-hd3FO4_LeQikmgMtGLtTpnmpTzDk5_3QMMPNg0jyYNH9MLok3f__wxP9Wx38BJ12cVQ</recordid><startdate>20220517</startdate><enddate>20220517</enddate><creator>Yu, Huibin</creator><creator>Peng, Chen</creator><creator>Zhang, Chi</creator><creator>Stoian, Ana M M</creator><creator>Tazi, Loubna</creator><creator>Brennan, Greg</creator><creator>Rothenburg, Stefan</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4339-9045</orcidid><orcidid>https://orcid.org/0000-0003-2494-6901</orcidid><orcidid>https://orcid.org/0000-0002-2430-272X</orcidid><orcidid>https://orcid.org/0000-0002-6687-7134</orcidid><orcidid>https://orcid.org/0000-0002-2525-8230</orcidid></search><sort><creationdate>20220517</creationdate><title>Maladaptation after a virus host switch leads to increased activation of the pro-inflammatory NF-κB pathway</title><author>Yu, Huibin ; 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| subjects | Animals Biological Sciences Crosstalk Depletion eIF-2 kinase eIF-2 Kinase - metabolism Host-Pathogen Interactions Inflammation Inhibition Interleukin 6 Kinases Metabolic Networks and Pathways Molecular modelling Mutants Myxoma Myxoma virus - genetics Myxoma virus - pathogenicity Myxomatosis Myxomatosis, Infectious - metabolism Myxomatosis, Infectious - virology NF-kappa B - metabolism NF-KappaB Inhibitor alpha - metabolism NF-κB protein Protein kinase R Proteins Rabbits Rabbits - virology Signal transduction Transfection Tumor necrosis factor-α Virulence Viruses |
| title | Maladaptation after a virus host switch leads to increased activation of the pro-inflammatory NF-κB pathway |
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