Coronavirus gene 7 counteracts host defenses and modulates virus virulence.
Transmissible gastroenteritis virus (TGEV) genome contains three accessory genes: 3a, 3b and 7. Gene 7 is only present in members of coronavirus genus a1, and encodes a hydrophobic protein of 78 aa. To study gene 7 function, a recombinant TGEV virus lacking gene 7 was engineered (rTGEV-Δ7). Both the...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-06-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3111541?pdf=render |
| _version_ | 1818827770570997760 |
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| author | Jazmina L G Cruz Isabel Sola Martina Becares Berta Alberca Joan Plana Luis Enjuanes Sonia Zuñiga |
| author_facet | Jazmina L G Cruz Isabel Sola Martina Becares Berta Alberca Joan Plana Luis Enjuanes Sonia Zuñiga |
| author_sort | Jazmina L G Cruz |
| collection | DOAJ |
| description | Transmissible gastroenteritis virus (TGEV) genome contains three accessory genes: 3a, 3b and 7. Gene 7 is only present in members of coronavirus genus a1, and encodes a hydrophobic protein of 78 aa. To study gene 7 function, a recombinant TGEV virus lacking gene 7 was engineered (rTGEV-Δ7). Both the mutant and the parental (rTGEV-wt) viruses showed the same growth and viral RNA accumulation kinetics in tissue cultures. Nevertheless, cells infected with rTGEV-Δ7 virus showed an increased cytopathic effect caused by an enhanced apoptosis mediated by caspase activation. Macromolecular synthesis analysis showed that rTGEV-Δ7 virus infection led to host translational shut-off and increased cellular RNA degradation compared with rTGEV-wt infection. An increase of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation and an enhanced nuclease, most likely RNase L, activity were observed in rTGEV-Δ7 virus infected cells. These results suggested that the removal of gene 7 promoted an intensified dsRNA-activated host antiviral response. In protein 7 a conserved sequence motif that potentially mediates binding to protein phosphatase 1 catalytic subunit (PP1c), a key regulator of the cell antiviral defenses, was identified. We postulated that TGEV protein 7 may counteract host antiviral response by its association with PP1c. In fact, pull-down assays demonstrated the interaction between TGEV protein 7, but not a protein 7 mutant lacking PP1c binding motif, with PP1. Moreover, the interaction between protein 7 and PP1 was required, during the infection, for eIF2α dephosphorylation and inhibition of cell RNA degradation. Inoculation of newborn piglets with rTGEV-Δ7 and rTGEV-wt viruses showed that rTGEV-Δ7 virus presented accelerated growth kinetics and pathology compared with the parental virus. Overall, the results indicated that gene 7 counteracted host cell defenses, and modified TGEV persistence increasing TGEV survival. Therefore, the acquisition of gene 7 by the TGEV genome most likely has provided a selective advantage to the virus. |
| first_indexed | 2024-12-19T00:48:50Z |
| format | Article |
| id | doaj.art-85cb9f8906254dc09f8d3e3f9abcfb99 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-19T00:48:50Z |
| publishDate | 2011-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-85cb9f8906254dc09f8d3e3f9abcfb992022-12-21T20:44:09ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742011-06-0176e100209010.1371/journal.ppat.1002090Coronavirus gene 7 counteracts host defenses and modulates virus virulence.Jazmina L G CruzIsabel SolaMartina BecaresBerta AlbercaJoan PlanaLuis EnjuanesSonia ZuñigaTransmissible gastroenteritis virus (TGEV) genome contains three accessory genes: 3a, 3b and 7. Gene 7 is only present in members of coronavirus genus a1, and encodes a hydrophobic protein of 78 aa. To study gene 7 function, a recombinant TGEV virus lacking gene 7 was engineered (rTGEV-Δ7). Both the mutant and the parental (rTGEV-wt) viruses showed the same growth and viral RNA accumulation kinetics in tissue cultures. Nevertheless, cells infected with rTGEV-Δ7 virus showed an increased cytopathic effect caused by an enhanced apoptosis mediated by caspase activation. Macromolecular synthesis analysis showed that rTGEV-Δ7 virus infection led to host translational shut-off and increased cellular RNA degradation compared with rTGEV-wt infection. An increase of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation and an enhanced nuclease, most likely RNase L, activity were observed in rTGEV-Δ7 virus infected cells. These results suggested that the removal of gene 7 promoted an intensified dsRNA-activated host antiviral response. In protein 7 a conserved sequence motif that potentially mediates binding to protein phosphatase 1 catalytic subunit (PP1c), a key regulator of the cell antiviral defenses, was identified. We postulated that TGEV protein 7 may counteract host antiviral response by its association with PP1c. In fact, pull-down assays demonstrated the interaction between TGEV protein 7, but not a protein 7 mutant lacking PP1c binding motif, with PP1. Moreover, the interaction between protein 7 and PP1 was required, during the infection, for eIF2α dephosphorylation and inhibition of cell RNA degradation. Inoculation of newborn piglets with rTGEV-Δ7 and rTGEV-wt viruses showed that rTGEV-Δ7 virus presented accelerated growth kinetics and pathology compared with the parental virus. Overall, the results indicated that gene 7 counteracted host cell defenses, and modified TGEV persistence increasing TGEV survival. Therefore, the acquisition of gene 7 by the TGEV genome most likely has provided a selective advantage to the virus.http://europepmc.org/articles/PMC3111541?pdf=render |
| spellingShingle | Jazmina L G Cruz Isabel Sola Martina Becares Berta Alberca Joan Plana Luis Enjuanes Sonia Zuñiga Coronavirus gene 7 counteracts host defenses and modulates virus virulence. PLoS Pathogens |
| title | Coronavirus gene 7 counteracts host defenses and modulates virus virulence. |
| title_full | Coronavirus gene 7 counteracts host defenses and modulates virus virulence. |
| title_fullStr | Coronavirus gene 7 counteracts host defenses and modulates virus virulence. |
| title_full_unstemmed | Coronavirus gene 7 counteracts host defenses and modulates virus virulence. |
| title_short | Coronavirus gene 7 counteracts host defenses and modulates virus virulence. |
| title_sort | coronavirus gene 7 counteracts host defenses and modulates virus virulence |
| url | http://europepmc.org/articles/PMC3111541?pdf=render |
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