An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.

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

doi:10.1371/journal.ppat.1004856

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.

Highlights

Invading pathogens induce acute inflammation when molecular signatures are detected by pattern recognition receptors (PRRs; e.g., RIG-I like receptors [RIG-I-like receptors (RLRs)] and Toll-like receptors [TLRs]) expressed on tissue-resident immune cells and non-immune cell types
We used gene expression and virus growth data from influenza-infected mice to determine how moderate and deadly influenza viruses may invoke unique inflammatory responses and the role these responses play in disease pathology
We found that the relationship between virus growth and the inflammatory response for all viruses tested can be characterized by ultrasensitive response in which the inflammatory response is gated until a threshold concentration of virus is exceeded in the lung after which strong inflammatory gene expression and cytokine production occurs

Summary

Introduction

Invading pathogens induce acute inflammation when molecular signatures are detected by pattern recognition receptors (PRRs; e.g., RIG-I like receptors [RLRs] and Toll-like receptors [TLRs]) expressed on tissue-resident immune cells and non-immune cell types. Other data indicate that influenza viruses that exhibit significant differences in pathogenicity stimulate qualitatively similar host responses that differ primarily at the level of magnitude and kinetics [17]. These studies have not revealed the mechanisms that account for the different profile dynamics observed in infections by high and low pathogenic viruses. Such information would aid in clarifying how some influenza viruses induce lethal disease, and the general mechanisms that regulate inflammatory balance

Results

Discussion

Conclusion