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Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice

Gammaherpesviruses encode proteins with homology to the cellular purine metabolic enzyme formyl-glycinamide-phosphoribosyl-amidotransferase (FGARAT), but the role of these viral FGARATs (vFGARATs) in the pathogenesis of a natural host has not been investigated. We report a novel role for the ORF75A...

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Autores principales: Van Skike, Nick D., Minkah, Nana K., Hogan, Chad H., Wu, Gary, Benziger, Peter T., Oldenburg, Darby G., Kara, Mehmet, Kim-Holzapfel, Deborah M., White, Douglas W., Tibbetts, Scott A., French, Jarrod B., Krug, Laurie T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811070/
https://www.ncbi.nlm.nih.gov/pubmed/29390024
http://dx.doi.org/10.1371/journal.ppat.1006843
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author Van Skike, Nick D.
Minkah, Nana K.
Hogan, Chad H.
Wu, Gary
Benziger, Peter T.
Oldenburg, Darby G.
Kara, Mehmet
Kim-Holzapfel, Deborah M.
White, Douglas W.
Tibbetts, Scott A.
French, Jarrod B.
Krug, Laurie T.
author_facet Van Skike, Nick D.
Minkah, Nana K.
Hogan, Chad H.
Wu, Gary
Benziger, Peter T.
Oldenburg, Darby G.
Kara, Mehmet
Kim-Holzapfel, Deborah M.
White, Douglas W.
Tibbetts, Scott A.
French, Jarrod B.
Krug, Laurie T.
author_sort Van Skike, Nick D.
collection PubMed
description Gammaherpesviruses encode proteins with homology to the cellular purine metabolic enzyme formyl-glycinamide-phosphoribosyl-amidotransferase (FGARAT), but the role of these viral FGARATs (vFGARATs) in the pathogenesis of a natural host has not been investigated. We report a novel role for the ORF75A vFGARAT of murine gammaherpesvirus 68 (MHV68) in infectious virion production and colonization of mice. MHV68 mutants with premature stop codons in orf75A exhibited a log reduction in acute replication in the lungs after intranasal infection, which preceded a defect in colonization of multiple host reservoirs including the mediastinal lymph nodes, peripheral blood mononuclear cells, and the spleen. Intraperitoneal infection rescued splenic latency, but not reactivation. The 75A.stop virus also exhibited defective replication in primary fibroblast and macrophage cells. Viruses produced in the absence of ORF75A were characterized by an increase in the ratio of particles to PFU. In the next round of infection this led to the alteration of early events in lytic replication including the deposition of the ORF75C tegument protein, the accelerated kinetics of viral gene expression, and induction of TNFα release and cell death. Infecting cells to deliver equivalent genomes revealed that ORF75A was required for initiating early events in infection. In contrast with the numerous phenotypes observed in the absence of ORF75A, ORF75B was dispensable for replication and pathogenesis. These studies reveal that murine rhadinovirus vFGARAT family members ORF75A and ORF75C have evolved to perform divergent functions that promote replication and colonization of the host.
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spelling pubmed-58110702018-02-28 Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice Van Skike, Nick D. Minkah, Nana K. Hogan, Chad H. Wu, Gary Benziger, Peter T. Oldenburg, Darby G. Kara, Mehmet Kim-Holzapfel, Deborah M. White, Douglas W. Tibbetts, Scott A. French, Jarrod B. Krug, Laurie T. PLoS Pathog Research Article Gammaherpesviruses encode proteins with homology to the cellular purine metabolic enzyme formyl-glycinamide-phosphoribosyl-amidotransferase (FGARAT), but the role of these viral FGARATs (vFGARATs) in the pathogenesis of a natural host has not been investigated. We report a novel role for the ORF75A vFGARAT of murine gammaherpesvirus 68 (MHV68) in infectious virion production and colonization of mice. MHV68 mutants with premature stop codons in orf75A exhibited a log reduction in acute replication in the lungs after intranasal infection, which preceded a defect in colonization of multiple host reservoirs including the mediastinal lymph nodes, peripheral blood mononuclear cells, and the spleen. Intraperitoneal infection rescued splenic latency, but not reactivation. The 75A.stop virus also exhibited defective replication in primary fibroblast and macrophage cells. Viruses produced in the absence of ORF75A were characterized by an increase in the ratio of particles to PFU. In the next round of infection this led to the alteration of early events in lytic replication including the deposition of the ORF75C tegument protein, the accelerated kinetics of viral gene expression, and induction of TNFα release and cell death. Infecting cells to deliver equivalent genomes revealed that ORF75A was required for initiating early events in infection. In contrast with the numerous phenotypes observed in the absence of ORF75A, ORF75B was dispensable for replication and pathogenesis. These studies reveal that murine rhadinovirus vFGARAT family members ORF75A and ORF75C have evolved to perform divergent functions that promote replication and colonization of the host. Public Library of Science 2018-02-01 /pmc/articles/PMC5811070/ /pubmed/29390024 http://dx.doi.org/10.1371/journal.ppat.1006843 Text en © 2018 Van Skike et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Van Skike, Nick D.
Minkah, Nana K.
Hogan, Chad H.
Wu, Gary
Benziger, Peter T.
Oldenburg, Darby G.
Kara, Mehmet
Kim-Holzapfel, Deborah M.
White, Douglas W.
Tibbetts, Scott A.
French, Jarrod B.
Krug, Laurie T.
Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice
title Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice
title_full Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice
title_fullStr Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice
title_full_unstemmed Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice
title_short Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice
title_sort viral fgarat orf75a promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811070/
https://www.ncbi.nlm.nih.gov/pubmed/29390024
http://dx.doi.org/10.1371/journal.ppat.1006843
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