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

An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.

Author information

1
ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
2
School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
3
ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; Laboratory for Disease Systems Modeling, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
4
ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; Department of Emerging Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
5
Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
6
ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; Laboratory of Veterinary Microbiology, Department of Veterinary Sciences, University of Miyazaki, Miyazaki, Japan.
7
ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
8
ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; The Systems Biology Institute, Tokyo, Japan.
9
ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; Laboratory for Disease Systems Modeling, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; The Systems Biology Institute, Tokyo, Japan; Okinawa Institute of Science and Technology, Okinawa, Japan.
10
ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Abstract

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.

PMID:
26046528
PMCID:
PMC4457877
DOI:
10.1371/journal.ppat.1004856
[Indexed for MEDLINE]
Free PMC Article

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