Open Access Research article

Distinct gene loci control the host response to influenza H1N1 virus infection in a time-dependent manner

Tatiana Nedelko1, Heike Kollmus1, Frank Klawonn23, Sabine Spijker5, Lu Lu46, Manuela Heßman17, Rudi Alberts1, Robert W Williams5 and Klaus Schughart1*

Author Affiliations

1 Department of Infection Genetics, Helmholtz Centre for Infection Research and University of Veterinary Medicine Hannover, 38124, Braunschweig, Germany

2 Department of Bioinformatics and Statistics, Helmholtz Centre for Infection Research, Braunschweig, Germany

3 Department of Computer Science, Ostfalia University of Applied Sciences, Wolfenbüttel, Germany

4 Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America

5 Department of Molecular and Cellular Neurobiology, Neuroscience Campus Amsterdam, Amsterdam, VU, the Netherlands

6 Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, China

7 Nycomed GmbH, Institute for Pharmacology and Preclinical Drug Safety, Barsbuettel-Willinghusen, Germany

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BMC Genomics 2012, 13:411  doi:10.1186/1471-2164-13-411

Published: 20 August 2012

Additional files

Additional file 1:

Table S1. Body weight loss from day 1 until day 7 for all strains showing the mean values, SEM per day and number of mice per strain analyzed.

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Additional file 2:

Figure S1. Differential susceptibility to influenza A infection among different BXD strains, parental strains and F1 generation. Rank-ordered strain distribution pattern illustrating the percentage of surviving mice per strain after influenza A infection for 53 BXD, parental DBA/2J and C57BL/6J strains and F1 (B6D2F1) mice for day 7 (A, trait ID: 13001) and day 8 (B, trait ID: 13002). Rank-ordered strain distribution pattern showing mean time to death for 53 BXD, parental DBA/2J and C57BL/6J strains and F1 (B6D2F1) mice (C, trait ID: 12996).

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Additional file 3:

Figure S2. Principal component analysis of all body weight traits. Percent contribution of principal components to the total variance for body weight traits from day 1 until day 7 p.i. PC1 contributes about 80% and PC2 about 10% to the total variance.

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Additional file 4:

Figure S3. Body weight changes in mock-infected C57BL/6J and DBA/2J mice. Female DBA/2J (n=4) and C57BL/6J (n=3) mice were intranasally inoculated with 25 μl PBS under anesthesia. Body weight changes for each group of treated mice at various days p.i. is shown with reference to the starting weight (% body weight). Data represent mean values +/- SEM.

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Additional file 5:

Figure S4. Genome-wide linkage analysis for survival after H1N1 infection at days 9 and 10 p.i. Analysis of survival from day 9 (A) and day 10 (B) after PR8 infection revealed suggestive QTLs on chromosomes 5, 16, 17 and 19. Interval mapping is shown across the entire genome as blue line representing the LRS scores; green line: DBA/2J alleles increase trait values; red line: C57BL/6J alleles increase trait values. Upper x-axis shows mouse chromosomes, lower x-axis shows physical map in mega bases for each chromosome, y-axis represents LRS score. The horizontal lines mark the genome-wide significant thresholds at p0.05 (red line) and suggestive thresholds at p0.37 (gray line).

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Additional file 6:

Figure S5. Pair Scan analysis of trait 13002. The table provides the breakdown of trait 13002 as an example for a pair scan analysis study that compares the fit of the alternative models. An analysis of this type can be regenerated rapidly on any of the traits presented in our manuscript.

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Additional file 7:

Figure S6. Scheme to identify potential candidate genes in the analyzed QTL intervals. The detailed steps are described in the main manuscript.

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Additional file 8:

Table S2. List of genes in the QTL intervals that were studied in detail. The QTLminer tool in GeneNetwork was to identify all genes in the QTL intervals and to obtain associated GO terms and KEGG pathways. All annotated genes within the QTL intervals that were expressed between day 1 and day 60 after infection of C57BL/6J mice with PR8M virus were further analyzed for the following attributes: genes that were up- or down-regulated in infected lungs after PR8M infection, genes carrying an insertion or deletion or a non-synonymous nucleotide change in the open reading frame, genes exhibiting a cis-expression QTL in the lung, and genes that were differentially expressed in C57BL/6J and DBA/2J mice in infected lungs between day 1 and day 8 p.i. Abbreviations: FS: frame shift in coding region, SNP: single nucleotide polymorphism, cis-eQTL: cis-regulated expression QTL, B6: C57BL/6J, D2: DBA/2J, ns: non-synonymous codons, stop_G: stop codon gained, stop_L: stop codon lost, DEL: deletion, INS: insertion; ns (…): number of non-synonymous codons. Legends: Expression d0-d60, log2 ≥8 at any day during infection; No: log2 8; ?: no expression data available. Regulation during infection (d0-d60): + - up or down regulation, genes that exhibited at least a 2-fold difference in changes of the expression levels in lungs of infected mice compared to non-infected controls; (+)(-): up-or down-regulation, genes that exhibited at least a 1.5-fold difference in changes of the expression levels in lungs of infected mice compared to the non-infected controls; no: no regulation. SNP: ns (.) number of non-synonymous codons; STOP_L: Stop codon lost, STOP_G: Stop codon gained; no: no SNPs between B6 and D2. Indel: DEL: Deletion; INS: Insertion; no: no INDEL. cisQTL: yes (…): LRS value has to be greater than ≥18; no: no QTL or LRS 18. diff expressed (B6-D2) during infection: Genes were defined as differentially expressed (log2 ≥8) at any day in infected lungs of C57BL/6J and DBA/2J; + -: Genes were defined as differentially expressed exhibiting at least a 2.0 difference in changes of the expression levels in infected lungs of C57BL/6J and DBA/2J; (+)(-) differentially expressed: Genes were defined as differentially expressed exhibiting at least a 1.5 difference in changes of the expression levels in infected lungs of C57BL/6J and DBA/2J; no: no regulation or not expressed; Score: the different attributes were counted.

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