Functional & Integrative Genomics

, Volume 12, Issue 1, pp 105–117 | Cite as

Differential pulmonary transcriptomic profiles in murine lungs infected with low and highly virulent influenza H3N2 viruses reveal dysregulation of TREM1 signaling, cytokines, and chemokines

  • Fransiskus X. Ivan
  • Jagath C. Rajapakse
  • Roy E. Welsch
  • Steve G. Rozen
  • T. Narasaraju
  • Gordon M. Xiong
  • Bevin P. Engelward
  • Vincent T. ChowEmail author
Original Paper


Investigating the relationships between critical influenza viral mutations contributing to increased virulence and host expression factors will shed light on the process of severe pathogenesis from the systems biology perspective. We previously generated a mouse-adapted, highly virulent influenza (HVI) virus through serial lung-to-lung passaging of a human influenza H3N2 virus strain that causes low virulent influenza (LVI) in murine lungs. This HVI virus is characterized by enhanced replication kinetics, severe lung injury, and systemic spread to major organs. Our gene microarray investigations compared the host transcriptomic responses of murine lungs to LVI virus and its HVI descendant at 12, 48, and 96 h following infection. More intense expression of genes associated with cytokine activity, type 1 interferon response, and apoptosis was evident in HVI at all time-points. We highlighted dysregulation of the TREM1 signaling pathway (an amplifier of cytokine production) that is likely to be upregulated in infiltrating neutrophils in HVI-infected lungs. The cytokine gene expression changes were corroborated by elevated levels of multiple cytokine and chemokine proteins in the bronchoalveolar lavage fluid of infected mice, especially at 12 h post-infection. Concomitantly, the downregulation of genes that mediate proliferative, developmental, and metabolic processes likely contributed to the lethality of HVI as well as lack of lung repair. Overall, our comparative transcriptomic study provided insights into key host factors that influence the dynamics, pathogenesis, and outcome of severe influenza.


Influenza virulence Severe lung damage Pulmonary transcriptomics TREM1 signaling Cytokine/chemokine dysregulation 



Financial support was provided by the National Medical Research Council, Singapore, Microbiology Vaccine Initiative, and Singapore-MIT Alliance. We are grateful to M. C. Phoon and Kelly Lau for technical assistance.

Conflicts of interest

The authors declare no conflicts of interest.

Supplementary material

10142_2011_247_MOESM1_ESM.docx (49 kb)
Fig. 1 A summary of overlap between expression of genes exhibiting significant infection, time, and interaction effects as analyzed by two-way ANOVA. (DOCX 49 kb)
10142_2011_247_MOESM2_ESM.docx (86 kb)
Fig. 2 Overall heatmap depicting differentially expressed genes at 12, 48, and 96 h post-infection. Genes include those with an absolute log expression ratio of >0.6 in at least one time-point after low virulent influenza (LVI) and highly virulent influenza (HVI) infection. (DOCX 86 kb)
10142_2011_247_MOESM3_ESM.docx (252 kb)
Fig. 3 Overview of type 1 interferon-stimulated gene expression patterns at 12, 48, and 96 h post-infection with low virulent influenza (LVI) and highly virulent influenza (HVI). (DOCX 252 kb)
10142_2011_247_MOESM4_ESM.docx (203 kb)
Fig. 4 Overview of apoptotic gene expression patterns at 12, 48, and 96 h post-infection with low virulent influenza (LVI) and highly virulent influenza (HVI). (DOCX 202 kb)


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Fransiskus X. Ivan
    • 1
    • 2
  • Jagath C. Rajapakse
    • 1
    • 2
  • Roy E. Welsch
    • 1
    • 5
  • Steve G. Rozen
    • 1
    • 4
  • T. Narasaraju
    • 3
  • Gordon M. Xiong
    • 3
  • Bevin P. Engelward
    • 5
  • Vincent T. Chow
    • 1
    • 3
    Email author
  1. 1.Computational and Systems Biology ProgramSingapore-MIT AllianceSingaporeSingapore
  2. 2.BioInformatics Research CentreNanyang Technological UniversitySingaporeSingapore
  3. 3.Infectious Diseases Program, Department of Microbiology, Yong Loo Lin School of Medicine, National University Health SystemNational University of SingaporeSingaporeSingapore
  4. 4.Duke-NUS Graduate Medical SchoolSingaporeSingapore
  5. 5.Massachusetts Institute of TechnologyCambridgeUSA

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