Journal Article An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation

Shoemaker, Jason E.  ,  Fukuyama, Satoshi  ,  Eisfeld, Amie J.  ,  Zhao, Dongming  ,  Kawakami, Eiryo  ,  Sakabe, Saori  ,  Maemura, Tadashi  ,  Gorai, Takeo  ,  Katsura, Hiroaki  ,  Muramoto, Yukiko  ,  Watanabe, Shinji  ,  Watanabe, Tokiko  ,  Fuji, Ken  ,  Matsuoka, Yukiko  ,  Kitano, Hiroaki  ,  Kawaoka, Yoshihiro

11 ( 6 )  , p.e1004856 , 2015-06-05 , Public Library of Science
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.

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