An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation

PLoS Pathog. 2015 Jun 5;11(6):e1004856. doi: 10.1371/journal.ppat.1004856. eCollection 2015 Jun.


Influenza viruses present major challenges to public health, evident by the 2009 influenza pandemic. Highly pathogenic influenza virus infections generally coincide with early, high levels of inflammatory cytokines that some studies have suggested may be regulated in a strain-dependent manner. However, a comprehensive characterization of the complex dynamics of the inflammatory response induced by virulent influenza strains is lacking. Here, we applied gene co-expression and nonlinear regression analysis to time-course, microarray data developed from influenza-infected mouse lung to create mathematical models of the host inflammatory response. We found that the dynamics of inflammation-associated gene expression are regulated by an ultrasensitive-like mechanism in which low levels of virus induce minimal gene expression but expression is strongly induced once a threshold virus titer is exceeded. Cytokine assays confirmed that the production of several key inflammatory cytokines, such as interleukin 6 and monocyte chemotactic protein 1, exhibit ultrasensitive behavior. A systematic exploration of the pathways regulating the inflammatory-associated gene response suggests that the molecular origins of this ultrasensitive response mechanism lie within the branch of the Toll-like receptor pathway that regulates STAT1 phosphorylation. This study provides the first evidence of an ultrasensitive mechanism regulating influenza virus-induced inflammation in whole lungs and provides insight into how different virus strains can induce distinct temporal inflammation response profiles. The approach developed here should facilitate the construction of gene regulatory models of other infectious diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Female
  • Flow Cytometry
  • Inflammation / genetics
  • Inflammation / immunology
  • Influenza A Virus, H1N1 Subtype* / genetics
  • Influenza A Virus, H1N1 Subtype* / immunology
  • Influenza A Virus, H1N1 Subtype* / pathogenicity
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Transcriptome
  • Virulence

Associated data

  • GEO/GSE63786

Grants and funding

This research was supported by the Japan Science and Technology Agency’s Exploratory Research for Advanced Technology (ERATO) program and Strategic Basic Research Programs. This work was also supported by the Japan Initiative for Global Research Network on Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by grants-in-aid from the Ministry of Health, Labour and Welfare, Japan; and by National Institute of Allergy and Infectious Diseases Public Health Service research grants. HKa is supported by JSPS Research Fellowships for young scientists. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.