Unknown,Transcriptomics,Genomics,Proteomics

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An overlapping protein-coding region in Influenza A Virus Segment 3 modulates the host response

ABSTRACT: Segment 3 of influenza A virus contains a second open reading frame accessed via robosomal frameshifting. The frameshift product, PA-Z, comprises the endonuclease domain of viral PA protein with C-terminal demain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model. The effect of PA-X deltions were examined using 2 separate mutant influenza viruses (1918-FS/1918-PCT1) and the results compared to wild-type 1918 influenza virus. Balb/c mice were infected and samples harvested at days 3, 5 and 8 days. Four animals/condition were used. Gene expression levels from infected animals were compared to mock animals.

ORGANISM(S): Mus musculus

SUBMITTER: kathie walters

PROVIDER: E-GEOD-38112 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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An overlapping protein-coding region in influenza A virus segment 3 modulates the host response.

Jagger B W BW Wise H M HM Kash J C JC Walters K-A KA Wills N M NM Xiao Y-L YL Dunfee R L RL Schwartzman L M LM Ozinsky A A Bell G L GL Dalton R M RM Lo A A Efstathiou S S Atkins J F JF Firth A E AE Taubenberger J K JK Digard P P

Science (New York, N.Y.) 20120628 6091

Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame ("X-ORF"), accessed via ribosomal frameshifting. The frameshift product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogeni ...[more]

PMID: 22745253

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Project description:While pandemic 2009 H1N1 influenza A viruses were responsible for numerous severe infections in humans, these viruses do not typically cause corresponding severe disease in mammalian models. However, the generation of a virulent 2009 H1N1 virus following serial lung passage in mice has allowed for the modeling of human lung pathology in this species. Genetic determinants of mouse-adapted 2009 H1N1 viral pathogenicity have been identified, but the molecular and signaling characteristics of the host response following infection with this adapted virus have not been described. Here, we compared the gene-expression response following infection of mice with A/CA/04/2009 (CA/04) or the virulent mouse-adapted strain (MA-CA/04). Microarray analysis revealed that increased pathogenicity of MA-CA/04 was associated with: (1) early and sustained inflammatory and interferon response that could be driven in part by interferon regulatory factors (IRFs) and increased NFM-oM-^AM-+B activation, as well as inhibition of the negative regulator TRIM24, (2) early and persistent infiltration of immune cells, including inflammatory macrophages, and (3) the absence of activation of lipid metabolism later in infection, that may be mediated by nuclear receptors inhibition, including PPARG, HNF1A and 4A, with pro-inflammatory consequences. Further investigation of these signatures in the host response to other H1N1 viruses of varied pathogenicity confirmed their general relevance for virulence of influenza virus and suggested that lung response to MA-CA/04 virus was similar to that following lethal H1N1 r1918 influenza virus. This study links for the first time differential activation of IRFs, nuclear receptors, and macrophage infiltration with influenza virulence in vivo. Six-to-eight-week-old female BALB/c mice were anesthetized and inoculated with 50 M-NM-<l of phosphate-buffered saline (PBS; Mock) or with 10^6 pfu of virus in a 50 M-NM-<l volume. Nine animals per condition group were used for tarray analysis, two or three animals per time point. There were seven condition groups: A/California/04/2009, MA1-A/California/04/2009, A/Mexico/4482/09, A/Brisbane/59/07, A/New Jersey/8/76, the reconstructed 1918 virus and timeM-bM-^@M-^Smatched mocks.

Dataset Information

An overlapping protein-coding region in Influenza A Virus Segment 3 modulates the host response

Publications

An overlapping protein-coding region in influenza A virus segment 3 modulates the host response.

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