ArticlePLoS pathogens2015
An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Network analysis of multivariate time series data in biological systems: methods and applications.Briefings in bioinformatics · 2025Article
- Attenuation of A(H7N9) influenza virus infection in mice exposed to cigarette smoke.Npj viruses · 2024Article
- The Identification Distinct Antiviral Factors Regulated Influenza Pandemic H1N1 Infection.International journal of microbiology · 2024Article
- Pleural macrophages translocate to the lung during infection to promote improved influenza outcomes.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Enhanced viral infectivity and reduced interferon production are associated with high pathogenicity for influenza viruses.PLoS computational biology · 2023Article
- Article
- The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murine influenza A virus infection model.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- IL-1 and TNFα Contribute to the Inflammatory Niche to Enhance Alveolar Regeneration.Stem cell reports · 2019Article
- Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics.Redox biology · 2019Article
- Article
- In vivo imaging of the pathophysiological changes and neutrophil dynamics in influenza virus-infected mouse lungs.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- C57BL/6J and C57BL/6NJ Mice Are Differentially Susceptible to Inflammation-Associated Disease Caused by Influenza A Virus.Frontiers in microbiology · 2018Article
- The cell surface mucin MUC1 limits the severity of influenza A virus infection.Mucosal immunology · 2017Article
- The highly pathogenic H5N1 influenza A virus down-regulated several cellular MicroRNAs which target viral genome.Journal of cellular and molecular medicine · 2017Article
- Integrating Transcriptomic and Proteomic Data Using Predictive Regulatory Network Models of Host Response to Pathogens.PLoS computational biology · 2016Article
- Weighted enrichment method for prediction of transcription regulators from transcriptome and global chromatin immunoprecipitation data.Nucleic acids research · 2016Article
- A North American H7N3 Influenza Virus Supports Reassortment with 2009 Pandemic H1N1 and Induces Disease in Mice without Prior Adaptation.Journal of virology · 2016Article
- Differential Biphasic Transcriptional Host Response Associated with Coevolution of Hemagglutinin Quasispecies of Influenza A Virus.Frontiers in microbiology · 2016Article
- Lethal influenza infection: Is a macrophage to blame?Expert review of anti-infective therapy · 2015Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.