Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Role for HA and the viral RNA polymerase complex in the virulence of the 1918 influenza virus

ABSTRACT: The goal of this experiment was to examine the biological properties of reassortant viruses between the 1918 virus and a contemporary human H1N1 virus to determine the role of hemagglutinin (HA) and the viral RNA polymerase complex of 1918 virus toward pathogenesis and abberant host responses in mice. Six- to eight-week-old female BALB/c mice were anesthetized and inoculated with 50 μl of phosphate-buffered saline (PBS; Mock) or with 10^6 pfu of virus in a 50 μl volume. There are a total of six biological conditions: wild-type 1918 virus (A/Brevig Mission/1/1918; 1918), wild-type K173 virus (A/Kawasaki/173/2001; K173), three reassortant viruses between 1918 and K173 viruses [1918HA/K173, 1918PB1/K173, and 1918(3P+NP)/K173], and mock-infected control animals. Nine animals per virus group were inoculated, and whole lungs were collected at 1, 3 and 5 days post-inoculation from three animals per virus group per time point. Two of three mice inoculated with 1918 virus and 1918HA/K173 virus died by day 5 post-inoculation. Six animals were inoculated with PBS. Whole lungs from two mock-infected animals per time point were collected and served as the uninfected reference. All samples were processed for lung gene expression analysis using oligonucleotide microarrays. Technical replicates were performed for 9 samples.

ORGANISM(S): Mus musculus

SUBMITTER: Michael Katze

PROVIDER: E-GEOD-44595 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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.

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Role for HA and the viral RNA polymerase complex in the virulence of the 1918 influenza virus

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