Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Mapping Clinical and Expression QTL in a Sex-Dependent Effect of Host Susceptibility to Influenza H3N2/HK/1/68-MA20

ABSTRACT: Seasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza (p-flu) that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to p-flu in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (cQTL) and lung expression QTL (eQTL) mapping identified candidate genes for two sex-specific QTLs on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the tumor necrosis factor receptor superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment. To identify eQTLs, we reanalyzed lung expression data previously obtained by Lee et al (2006) on MGU74Av2 microarrays (Affymetrix) for 54 mice (13BcA, 12AcB, B6 and A/J mice in duplicate) using Custom CDFv12 to reorganize oligonucleotide probes based on the latest genome and transcriptome information. We inferred an A/J or B6 strain of origin for each gene based on the genotype of surrounding markers with a call rate of 96.7%. If a gene was in between A/J and B6 markers for a given RCS, it was coded as NA. Expression values were normalized using the Robust Multi-array Analysis (RMA) for Affymetrix gene chips. To define the association between differentially expressed genes and genotypes, ANOVA was conducted on a per-gene basis using the linear model Expression ~ DSO + BG + DSO*BG, where background (BG) and donor strain of origin (DSO) were coded as binary phenotypes corresponding to A/J or B6. The cutoff for genome-wide significance was computed using the BenjaminiM-bM-^@M-^SHochberg correction. For reference, the paper by Lee (2006): http://www.ncbi.nlm.nih.gov/pubmed/16449383

ORGANISM(S): Mus musculus

SUBMITTER: Rob Sladek

PROVIDER: E-GEOD-35888 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68.

Boivin Gregory A GA Pothlichet Julien J Skamene Emil E Brown Earl G EG Loredo-Osti J Concepción JC Sladek Robert R Vidal Silvia M SM

Journal of immunology (Baltimore, Md. : 1950) 20120316 8

Seasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza that reproduces the ...[more]

PMID: 22427645

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Project description:In vertebrates, non-lens bg-crystallins are widely expressed in various tissues, but their functions are unknown. The molecular mechanisms of trefoil factors, initiators of mucosal healing and being greatly involved in tumorigenesis, have remained elusive.A naturally existing 72-kDa complex of non-lens bg-crystallin (a-subunit) and trefoil factor (b-subunit), named bg-CAT, was identified from frog Bombina maxima skin secretions. Its a-subunit and b-subunit (containing three trefoil factor domains), with a non-covalently linked form of ab2, show significant sequence homology to ep37 proteins, a group of non-lens bg-crystallins identified in newt Cynops pyrrhogaster and mammalian trefoil factors, respectively. The bg-CAT showed multiple cellular effects on human umbilical vein endothelial cells. Low dosages of bg-CAT (25-50 pM) were able to stimulate cell migration and wound healing. At high concentrations, it induced cell detachment (EC50 10 nM) and apoptosis. The bg-CAT was rapidly endocytosed via intracellular vacuole formation. Under confocal microscope, some of the vacuoles were translocated to nucleus and partially fused with nuclear membraneï®. However, what exactly target of bg-CAT act on HUVECs nuclear is still unknown. Primary cultured HUVECs treated with bg-CAT (25 nM, 2 h) were selected for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain the genome wide level of significant differential gene expression induced by bg-CAT on HUVECs in order to get clues about bg-CAT action mechanisms. These findings illustrate novel cellular functions of non-lens bg-cyrstallins and action mechanism via association with trefoil factors, serving as clues for investigating the possible occurrence of similar molecules and action mechanisms in mammals. Experiment Overall Design: We used microarrays to analysis genome wide level of significant differential gene expression induced by bg-CAT on HUVECs.Four independent biological replicates of HUVECs treated with bg-CAT (25 nM, 2 h) were compared with normal control by SAM. The significant differential expression of 123 genes (fold changeâ¥3, q value =0, FDR (false discovery rate)=0). 121 genes were up-regulated, among which members of nuclear receptor subfamily 4 (NR4A) were the most prominent. Only 2 genes were down-regulated (including collagen type I) (Supporting information Fig. S1 and Table S1 in accompanying publication). Members of NR4A exhibit differential roles in determining cell growth or cell death depending on its location in the nucleus or mitochondria. NR4A1 (also called Nur77, TR3) mediates cell apoptosis through translocation from nucleus to mitochondria and induction of cytochrome c releasing . Significant activation of NR4A members suggests these orphan nuclear receptors may be involved in the mediation of bg-CAT biological functions, like proapoptotic action of the protein at high concentrations. Up-regulated expression of a number of matrix metalloproteinases by bg-CAT could facilitate cell migration and detachment. The bg-CAT also induced the expression of a number of cytokines, including interleukin 1, interleukin 8 and interleukin 6, as well as various chemokines in HUVECs. These data provide clues for study in detail of molecular pathways through which bg-CAT exerts its biological functions.

Dataset Information

Mapping Clinical and Expression QTL in a Sex-Dependent Effect of Host Susceptibility to Influenza H3N2/HK/1/68-MA20

Publications

Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68.

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