Unknown,Transcriptomics,Genomics,Proteomics

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Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus.

ABSTRACT: This study revealed important similarities but also critical differences between the H5N1 and 1918-reassortant viruses, highlighting aspects of the host–pathogen interface caused by highly virulent influenza viruses. Animals assigned to 4 experimental groups (n = 8) matched for age, weight, and sex, were inoculated by intratracheal, intranasal, tonsillar, and conjunctival routes with a total of 107 pfu of A/Vietnam/1203/2004 (H5N1) virus, A/Texas/36/91 (H1N1) virus or reassortants of this virus containing either 2 (HA, NA) or 3 (HA, NA, NS) genes from the 1918 virus. Two animals per group were scheduled for sacrifice on days 1, 2, 4, and 7. Two additional animals were used as uninfected control animals and killed on day 7. Oligoarray analyses consisted of comparing array profiles of individual lung samples (with representative pathology and degree of infection) from infected animals to pooled equal masses of mRNA from all lung lobes of 7 reference cynomolgus macaques obtained through the tissue program of the University of Washington National Primate Research Center. There are 2 technical array replicates fro each sample.

ORGANISM(S): Macaca fascicularis

SUBMITTER: Richard Green

PROVIDER: E-GEOD-33351 | 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: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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Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus.

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