title: An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.
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.
authors.affiliation: 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.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Shoemaker
authors.affiliation: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuyama
authors.affiliation: School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Amie J
authors.initials: AJ
authors.lastname: Eisfeld
authors.affiliation: 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.
authors.forename: Dongming
authors.initials: D
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Eiryo
authors.initials: E
authors.lastname: Kawakami
authors.affiliation: 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.
authors.forename: Saori
authors.initials: S
authors.lastname: Sakabe
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Maemura
authors.affiliation: School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Takeo
authors.initials: T
authors.lastname: Gorai
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Katsura
authors.affiliation: 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.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Muramoto
authors.affiliation: 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.
authors.forename: Shinji
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: 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.
authors.forename: Tokiko
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Fuji
authors.affiliation: ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan; The Systems Biology Institute, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Matsuoka
authors.affiliation: 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.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitano
authors.affiliation: 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.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome; D014774:Virulence