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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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Citation and License

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

Published: 20 August 2012

Abstract

Background

There is strong but mostly circumstantial evidence that genetic factors modulate the severity of influenza infection in humans. Using genetically diverse but fully inbred strains of mice it has been shown that host sequence variants have a strong influence on the severity of influenza A disease progression. In particular, C57BL/6J, the most widely used mouse strain in biomedical research, is comparatively resistant. In contrast, DBA/2J is highly susceptible.

Results

To map regions of the genome responsible for differences in influenza susceptibility, we infected a family of 53 BXD-type lines derived from a cross between C57BL/6J and DBA/2J strains with influenza A virus (PR8, H1N1). We monitored body weight, survival, and mean time to death for 13 days after infection. Qivr5 (quantitative trait for influenza virus resistance on chromosome 5) was the largest and most significant QTL for weight loss. The effect of Qivr5 was detectable on day 2 post infection, but was most pronounced on days 5 and 6. Survival rate mapped to Qivr5, but additionally revealed a second significant locus on chromosome 19 (Qivr19). Analysis of mean time to death affirmed both Qivr5 and Qivr19. In addition, we observed several regions of the genome with suggestive linkage. There are potentially complex combinatorial interactions of the parental alleles among loci. Analysis of multiple gene expression data sets and sequence variants in these strains highlights about 30 strong candidate genes across all loci that may control influenza A susceptibility and resistance.

Conclusions

We have mapped influenza susceptibility loci to chromosomes 2, 5, 16, 17, and 19. Body weight and survival loci have a time-dependent profile that presumably reflects the temporal dynamic of the response to infection. We highlight candidate genes in the respective intervals and review their possible biological function during infection.