Unknown,Transcriptomics,Genomics,Proteomics

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Comparative transcriptomic analysis of acute host responses during 2009 pandemic H1N1 influenza infection in mouse, macaque, and swine (swine dataset)

ABSTRACT: 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.

ORGANISM(S): Sus scrofa

SUBMITTER: Richard Green

PROVIDER: E-GEOD-40847 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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:This study used virological, histological, and global gene expression data to compare the virulence of two 2009 pH1N1 isolates from human (A/California/04/2009) and swine (A/swine/Alberta/25/2009) to that of a 1918-like classical swine influenza virus (A/swine/Iowa/1930) in a pig model of infection. The overall goal of this study was to characterize the clinical, histological, virological and global gene expression responses to three distinct influenza A isolates in an experimental pig model of influenza infection. We compared the pathogenesis of two pH1N1 viruses, one derived from a human patient (A/CA/04/09 [CA09]) and the other from swine (A/swine/Alberta/25/2009 [Alb09]), with that of the 1918-like classical swine influenza virus (A/swine/Iowa/1930 [IA30]) in the pig model. Both pH1N1 isolates induced clinical symptoms such as coughing, sneezing, decreased activity, fever, and labored breathing in challenged pigs, but IA30 virus did not cause any clinical symptoms except fever. Although both the pH1N1 viruses and the IA30 virus caused lung lesions, the pH1N1 viruses were shed from the nasal cavities of challenged pigs whereas the IA30 virus was not. Microarray was used to assess global gene expression in the lungs at 3 and 5 days post-infection. Crossbred pigs fwere obtained from a healthy herd free of SIV and porcine reproductive and respiratory syndrome virus. These studies included two experiments: the classical H1N1 SIV (IA30) study was completed at Kansas State University's biosafety level 2 (BSL-2) facility in compliance with the Institutional Animal Care and Use Committee at Kansas State University, and the pH1N1 virus study was completed at the Central States Research Center (CSRC), Inc., BSL-3 facility (Oakland, NE), in compliance with the Institutional Animal Care and Use Committee at CSRC. In each experiment, 10 pigs were inoculated with noninfectious cell culture supernatant as controls. For the classical H1N1 SIV experiment, 10 4-week-old crossbred pigs were inoculated intratracheally with 10^6 50% tissue culture infective doses (TCID50)/pig of egg-derived IA30 virus. For the pH1N1 virus experiment, 10 4-week-old crossbred pigs were inoculated intratracheally with 10^6 TCID50/pig of either egg-derived CA/09 or Alb/09 virus. Five animals per group were euthanized at 3 and 5 days postinfection (dpi), respectively.

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.

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.

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Comparative transcriptomic analysis of acute host responses during 2009 pandemic H1N1 influenza infection in mouse, macaque, and swine (swine dataset)

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