A novel genetic locus linked to pro-inflammatory cytokines after virulent H5N1 virus infection in mice

BMC Genomics

Richard J Webby²  David S Sinasac³  Robert W Williams⁴  Adrianus CM Boon¹ 

[1]Departments of Internal Medicine, Division of Infectious Diseases, Molecular Microbiology and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA

[2]Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA

[3]Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada

[4]Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA

关键词: Quantitative trait locus analysis;    BXD;    H5N1 influenza virus;   

Others  :  1091228
DOI  :  10.1186/1471-2164-15-1017

 received in 2014-06-03, accepted in 2014-10-22,  发布年份 2014

【 摘 要 】

Background

Genetic variation in the human population is a key determinant of influenza disease severity. A single nucleotide polymorphism in the antiviral gene IFITM3 was linked to outcomes during the 2009 H1N1 pandemic. To identify variant host genes associated with increased virus replication and severe disease, we performed a quantitative trait locus analysis on pro-inflammatory cytokine production 48 hours after intranasal infection with highly pathogenic H5N1 influenza virus.

Results

Pro-inflammatory cytokines CCL2, TNFα and IFN-α, were measured by ELISA in lung homogenates of DBA/2J (D2), C57BL/6J (B6) and 44 different BXD recombinant inbred mouse strains. Virus titer was also assessed in a subset of these animals. CCL2 (8-fold), TNFα (24-fold) and IFN-α (8-fold) concentrations varied significantly among the different BXD RI strains. Importantly, cytokine concentration correlated very well (r =0.86-0.96, P <0.0001) with virus titer suggesting that early cytokine production is due to increased virus infection and replication. Linkage analysis of cytokine concentration revealed a significant locus on chromosome 6 associated with differences in TNFα, IFN-α and CCL2 cytokine concentration (LRS =26). This locus accounted for nearly 20% of the observed phenotypic variation in the BXD population studied. Sequence and RNA expression analysis identified several candidate host genes containing missense mutations or deletions; Samd9l, Ica1, and Slc25a13. To study the role of Slc25a13, we obtained Slc25a13 knockout line, but upon challenge with H5N1 influenza virus observed no effect on CCL2 production, or morbidity and mortality.

Conclusion

A novel genetic locus on chromosome 6 modulates early pro-inflammatory cytokine production and virus replication after highly pathogenic influenza virus infection. Candidate genes, Samd9l and Ica1, may be important for the control of influenza virus infection and pathogenesis.

【 授权许可】

   
2014 Boon et al.; licensee BioMed Central Ltd.

【 图 表 】

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