Integrated analysis of mRNA-seq and miRNA-seq for host susceptibilities to influenza A (H7N9) infection in inbred mouse lines
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Host genetic factors play an important role in diverse host outcomes after influenza A (H7N9) infection. Studying differential responses of inbred mouse lines with distinct genetic backgrounds to influenza virus infection could substantially increase our understanding of the contributory roles of host genetic factors to disease severity. Here, we utilized an integrated approach of mRNA-seq and miRNA-seq to investigate the transcriptome expression and regulation of host genes in C57BL/6J and DBA/2J mouse strains during influenza virus infection. The differential pathogenicity of influenza virus in C57BL/6J and DBA/2J has been fully demonstrated through immunohistochemical staining, histopathological analyses, and viral replication assessment. A transcriptional molecular signature correlates to differential host response to infection has been uncovered. With the introduction of temporal expression pattern analysis, we demonstrated that host factors responsible for influenza virus replication and host–virus interaction were significantly enriched in genes exhibiting distinct temporal dynamics between different inbred mouse lines. A combination of time-series expression analysis and temporal expression pattern analysis has provided a list of promising candidate genes for future studies. An integrated miRNA regulatory network from both mRNA-seq and miRNA-seq revealed several regulatory modules responsible for regulating host susceptibilities and disease severity. Overall, a comprehensive framework for analyzing host susceptibilities to influenza infection was established by integrating mRNA-seq and miRNA-seq data of inbred mouse lines. This work suggests novel putative molecular targets for therapeutic interventions in seasonal and pandemic influenza.
KeywordsInfluenza (H7N9) virus Host susceptibilities mRNA-seq miRNA-seq Inbred mouse lines Temporal dynamics
non-negative matrix factorization
principle component analysis
differentially expressed genes
dynamic time warping maximal information coefficient
miRNA-mRNA interaction weight
- GGIW matrix
gene–gene interaction weight
Y.Q.S, M.L.Y., K.Y.Y., K.K.W.T., S.H., and S.B. designed research; L.J., Z.G.Z., H.W.L.W., Z.Y., NG., and D.SM.W. performed experiments; S.B., X.Z, and Y.F. analyzed results; and Y.Q.S, M.L.Y., S.B., and X.Z wrote the paper. All authors read and approved the final manuscript.
Compliance with ethical standards
Ethics approval and consent to participate
This study was approved by the Committee of the Use of Live Animals in Teaching and Research (CULATR 3275-14).
Consent for publication
The authors declare that they have no competing interests.
- Boivin GA, Pothlichet J, Skamene E, Brown EG, Loredo-Osti JC, Sladek R, Vidal SM (2012) Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68. J Immunol 188:3949–3960. https://doi.org/10.4049/jimmunol.1103320 CrossRefPubMedGoogle Scholar
- Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ (2009) The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile Virus, and Dengue Virus. Cell 139:1243–1254. https://doi.org/10.1016/j.cell.2009.12.017 CrossRefPubMedPubMedCentralGoogle Scholar
- Dhillon IS, Sra S (2005) Generalized nonnegative matrix approximations with Bregman divergences. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.861.820&rep=rep1&type=pdf
- Ferris MT, Aylor DL, Bottomly D, Whitmore AC, Aicher LD, Bell TA, Bradel-Tretheway B, Bryan JT, Buus RJ, Gralinski LE, Haagmans BL, McMillan L, Miller DR, Rosenzweig E, Valdar W, Wang J, Churchill GA, Threadgill DW, McWeeney SK, Katze MG, Pardo-Manuel de Villena F, Baric RS, Heise MT (2013) Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathogens 9:e1003196. https://doi.org/10.1371/journal.ppat.1003196 CrossRefPubMedPubMedCentralGoogle Scholar
- Fujioka Y, Tsuda M, Hattori T, Sasaki J, Sasaki T, Miyazaki T, Ohba Y (2011) The Ras-PI3K signaling pathway is involved in clathrin-independent endocytosis and the internalization of influenza viruses. PloS One 6:e16324. https://doi.org/10.1371/journal.pone.0016324 CrossRefPubMedPubMedCentralGoogle Scholar
- Geiss GK, An MC, Bumgarner RE, Hammersmark E, Cunningham D, Katze MG (2001) Global impact of influenza virus on cellular pathways is mediated by both replication-dependent and -independent events. J Virol 75:4321–4331. https://doi.org/10.1128/Jvi.75.9.4321-4331.2001 CrossRefPubMedPubMedCentralGoogle Scholar
- Lam TT-Y et al. (2013) The genesis and source of the H7N9 influenza viruses causing human infections in China. Nature advance online publication. doi: https://doi.org/10.1038/nature12515. http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature12515.html#supplementary-information
- Nencioni L, de Chiara G, Sgarbanti R, Amatore D, Aquilano K, Marcocci ME, Serafino A, Torcia M, Cozzolino F, Ciriolo MR, Garaci E, Palamara AT (2009) Bcl-2 expression and p38MAPK activity in cells infected with influenza A virus: impact on virally induced apoptosis and viral replication. J Biol Chem 284:16004–16015. https://doi.org/10.1074/jbc.M900146200 CrossRefPubMedPubMedCentralGoogle Scholar
- Parnell G, McLean A, Booth D, Huang S, Nalos M, Tang B (2011) Aberrant cell cycle and apoptotic changes characterise severe influenza A infection—a meta-analysis of genomic signatures in circulating leukocytes. PloS One 6:e17186. https://doi.org/10.1371/journal.pone.0017186 CrossRefPubMedPubMedCentralGoogle Scholar
- Pommerenke C, Wilk E, Srivastava B, Schulze A, Novoselova N, Geffers R, Schughart K (2012) Global transcriptome analysis in influenza-infected mouse lungs reveals the kinetics of innate and adaptive host immune responses. PloS One 7:e41169. https://doi.org/10.1371/journal.pone.0041169 CrossRefPubMedPubMedCentralGoogle Scholar
- Tandon R, Sra S (2010) Sparse nonnegative matrix approximation: new formulations and algorithms. http://www.cyberneum.de/fileadmin/user_upload/files/publications/MPIK-TR-193_.pdf
- Tsuno A, Miyoshi K, Tsujii R, Miyakawa T, Mizuta K (2000) RRS1, a conserved essential gene, encodes a novel regulatory protein required for ribosome biogenesis in Saccharomyces cerevisiae. Mol Cell Biol 20:2066–2074. https://doi.org/10.1128/Mcb.20.6.2066-2074.2000 CrossRefPubMedPubMedCentralGoogle Scholar
- Xiong X et al (2013) Receptor binding by an H7N9 influenza virus from humans. Nature 499:496–499. https://doi.org/10.1038/nature12372 http://www.nature.com/nature/journal/v499/n7459/abs/nature12372.html#supplementary-information CrossRefPubMedGoogle Scholar
- Yeung M-L et al (2016) MERS coronavirus induces apoptosis in kidney and lung by upregulating Smad7 and FGF2. Nature Microbiol 1:16004. https://doi.org/10.1038/nmicrobiol.2016.4 http://www.nature.com/articles/nmicrobiol20164#supplementary-information CrossRefGoogle Scholar
- Zhou J et al. (2013) Biological features of novel avian influenza A (H7N9) virus. Nature advance online publication doi: https://doi.org/10.1038/nature12379. http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature12379.html#supplementary-information