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Gene expression profiling of M. mulatta (Rhesus macaques) infected with H1N1 and pH1N1 influenza

ABSTRACT: Annually, influenza A viruses circulate the world causing wide-spread sickness, economic loss, and death. One way to better defend against influenza virus-induced disease may be to develop novel host-based therapies, targeted at mitigating viral pathogenesis through the management of virus-dysregulated host functions. However, mechanisms that govern aberrant host responses to influenza virus infection remain incompletely understood. We previously showed that the pandemic H1N1 virus influenza A/California/04/2009 (H1N1; CA04) has enhanced pathogenicity in the lungs of cynomolgus macaques relative to a seasonal influenza virus isolate (A/Kawasaki/UTK-4/2009 (H1N1; KUTK4)). Here, we used microarrays to identify host gene sequences that were highly differentially expressed (DE) in CA04-infected macaque lungs, and we employed a novel strategy – combining functional and pathway enrichment analyses, transcription factor binding site enrichment analysis and protein-protein interaction data – to create a CA04 differentially regulated host response network. This network describes enhanced viral RNA sensing, immune cell signaling and cell cycle arrest in CA04-infected lungs, and highlights a novel, putative role for the MYC-associated zinc finger (MAZ) transcription factor in regulating these processes.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE39018 | GEO | 2012/10/01

SECONDARY ACCESSION(S): PRJNA169613

REPOSITORIES: GEO

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Project description:Annually, influenza A viruses circulate the world causing wide-spread sickness, economic loss, and death. One way to better defend against influenza virus-induced disease may be to develop novel host-based therapies, targeted at mitigating viral pathogenesis through the management of virus-dysregulated host functions. However, mechanisms that govern aberrant host responses to influenza virus infection remain incompletely understood. We previously showed that the pandemic H1N1 virus influenza A/California/04/2009 (H1N1; CA04) has enhanced pathogenicity in the lungs of cynomolgus macaques relative to a seasonal influenza virus isolate (A/Kawasaki/UTK-4/2009 (H1N1; KUTK4)). Here, we used microarrays to identify host gene sequences that were highly differentially expressed (DE) in CA04-infected macaque lungs, and we employed a novel strategy M-bM-^@M-^S combining functional and pathway enrichment analyses, transcription factor binding site enrichment analysis and protein-protein interaction data M-bM-^@M-^S to create a CA04 differentially regulated host response network. This network describes enhanced viral RNA sensing, immune cell signaling and cell cycle arrest in CA04-infected lungs, and highlights a novel, putative role for the MYC-associated zinc finger (MAZ) transcription factor in regulating these processes. Lung tissues used for microarray studies were obtained from 13 female cynomolgus macaques infected with influenza viruses. 6 animals were inoculated with influenza A/California/04/2009 and 6 animals were inoculated with influenza A/Kawasaki/UTK-4/2009. 1 uninfected animal served as a negative control. On days 3 and 7 post-infection (p.i.), lung tissues were harvested from the middle and lower lung lobes of 3animals in each infection group (N = 26 total samples were collected, 3 samples were removed from the study due to low RNA quality). All but 3 samples were collected from visually apparent virus-induced gross lesions. Two lung tissue samples were obtained from middle and lower lobes of the uninfected animal at the start of the experiment.

Project description:Background: The 2009 pandemic H1N1 influenza virus emerged in swine and quickly became a major global health threat. In mouse, non-human primate, and swine infection models, the pH1N1 virus efficiently replicates in the lung and induces pro-inflammatory host responses; however, whether similar or different cellular pathways were impacted by pH1N1 virus across independent infection models remains to be further defined. To address this, we have performed a comparative transcriptomic analysis of acute host responses to a single pH1N1 influenza virus, A/California/04/2009 (CA04), in the lung of mice, macaques and swine. Results: Despite similarities in the clinical course, we observed differences in inflammatory molecules elicited, and the kinetics of their gene expression changes across all three species. The retinoid X receptor (RXR) signaling pathway controlling pro-inflammatory and metabolic processes was differentially regulated during infection in each species, though the heterodimeric RXR partner, pathway associated signaling molecules, and gene expression patterns differed in each species. Conclusions: By comparing transcriptional changes in the context of clinical and virological measures, we identified differences in the host transcriptional response to pH1N1 virus across independent models of acute infection. Antiviral resistance and the emergence of new influenza viruses have placed more focus on developing drugs that target the immune system. Underlying overt clinical disease are molecular events that suggest therapeutic targets identified in one host may not be appropriate in another. The goal of this experiment was to use global gene expression profiling to understand swine lung host responses to pandemic H1N1 influenza A/Californica/04/2009 (CA04) virus infection and compare acute host responses across independent species. Four-week-old crossbred pigs (Sus Scrofa) were inoculated intratracheally with either 10^6 TCID50/pig egg-derived 2009 pandemic influenza A/California/04/2009 virus (n = 5) or mock inoculated with non-infectious cell culture supernatant (control; n = 4). Animals were euthanized on day 7 post-infection and lung samples were used for microarray.

Project description:Background: The 2009 pandemic H1N1 influenza virus emerged in swine and quickly became a major global health threat. In mouse, non-human primate, and swine infection models, the pH1N1 virus efficiently replicates in the lung and induces pro-inflammatory host responses; however, whether similar or different cellular pathways were impacted by pH1N1 virus across independent infection models remains to be further defined. To address this, we have performed a comparative transcriptomic analysis of acute host responses to a single pH1N1 influenza virus, A/California/04/2009 (CA04), in the lung of mice, macaques and swine. Results: Despite similarities in the clinical course, we observed differences in inflammatory molecules elicited, and the kinetics of their gene expression changes across all three species. The retinoid X receptor (RXR) signaling pathway controlling pro-inflammatory and metabolic processes was differentially regulated during infection in each species, though the heterodimeric RXR partner, pathway associated signaling molecules, and gene expression patterns differed in each species. Conclusions: By comparing transcriptional changes in the context of clinical and virological measures, we identified differences in the host transcriptional response to pH1N1 virus across independent models of acute infection. Antiviral resistance and the emergence of new influenza viruses have placed more focus on developing drugs that target the immune system. Underlying overt clinical disease are molecular events that suggest therapeutic targets identified in one host may not be appropriate in another. The goal of this experiment was to use global gene expression profiling to understand non-human primate lung cellular responses to pandemic H1N1 influenza A/California/04/2009 virus infection. Four-to-fifteen-year-old cynomologous macaques were infected with CA04 virus (n = 4) under anesthesia through a combination of intratracheal (4 ml), intranasal (0.5 ml per nostril), conjunctival (0.5 ml per eyelid) and oral (1 ml) routes with a suspension containing 10^6 TCID50/ml (total infectious dose was 7x10^6 TCID50). Animals were euthanized on 1 and 6 days post-inoculation (n = 2 per time point), and total RNA was extracted from lung samples and analyzed by microarray. Pooled RNA from lungs of uninfected animals served as the reference.

Project description:Background: The 2009 pandemic H1N1 influenza virus emerged in swine and quickly became a major global health threat. In mouse, non-human primate, and swine infection models, the pH1N1 virus efficiently replicates in the lung and induces pro-inflammatory host responses; however, whether similar or different cellular pathways were impacted by pH1N1 virus across independent infection models remains to be further defined. To address this, we have performed a comparative transcriptomic analysis of acute host responses to a single pH1N1 influenza virus, A/California/04/2009 (CA04), in the lung of mice, macaques and swine. Results: Despite similarities in the clinical course, we observed differences in inflammatory molecules elicited, and the kinetics of their gene expression changes across all three species. The retinoid X receptor (RXR) signaling pathway controlling pro-inflammatory and metabolic processes was differentially regulated during infection in each species, though the heterodimeric RXR partner, pathway associated signaling molecules, and gene expression patterns differed in each species. Conclusions: By comparing transcriptional changes in the context of clinical and virological measures, we identified differences in the host transcriptional response to pH1N1 virus across independent models of acute infection. Antiviral resistance and the emergence of new influenza viruses have placed more focus on developing drugs that target the immune system. Underlying overt clinical disease are molecular events that suggest therapeutic targets identified in one host may not be appropriate in another. The goal of this experiment was to use global gene expression profiling to understand mouse lung cellular responses to pandemic H1N1 influenza A/Californica/04/2009 virus infection. Six-to-eight-week-old female BALB/c mice were anesthetized and inoculated with either 50 Î¼l of phosphate-buffered saline (PBS; Mock) or with 10^6 pfu of pandemic H1N1 influenza A/California/04/2009 virus in a 50 Î¼l volume, and whole lungs were collected at days 1, 3 and 5 post-inoculation. Lung samples from 9 animals for the infection group were used for array analysis, three animals per time point. Lung samples from 8 animals for the mock group were used for array analysis, three animals for the day 1 and 3 time points and 2 animals for the day 5 time point.

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Gene expression profiling of M. mulatta (Rhesus macaques) infected with H1N1 and pH1N1 influenza

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