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Title

Coronavirus gene 7 counteracts host defenses and modulates virus virulence

AuthorsCruz, Jazmina L. G.; Solá Gurpegui, Isabel ; Becares, Martina ; Alberca, Berta; Enjuanes Sánchez, Luis CSIC ORCID ; Zúñiga Lucas, Sonia CSIC ORCID
Issue DateJun-2011
PublisherPublic Library of Science
CitationPLoS Pathogens 7(6): e1002090 (2011)
AbstractTransmissible 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.
Publisher version (URL)http://dx.doi.org/10.1371/journal.ppat.1002090
URIhttp://hdl.handle.net/10261/204281
DOI10.1371/journal.ppat.1002090
Identifiersdoi: 10.1371/journal.ppat.1002090
issn: 1553-7366
e-issn: 1553-7374
Appears in Collections:(VICYT) Colección Especial COVID-19
(CNB) Artículos

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