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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
Published on: December 10, 2013
Neuregulin-1 prevents death from a normally lethal respiratory viral infection
Syed-Rehan A Hussain1,2, Michelle Rohlfing1,2, Jennifer Santoro1,2
1Division of Allergy and Immunology, Nationwide Children's Hospital - The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
Abstract:
Respiratory infections with RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen, Sendai virus (SeV), which is similar to RSV, mice made atopic with house dust mite survived a normally lethal SeV infection. One protein that we found markedly elevated in the lungs and bronchoalveolar lavage fluid of atopic mice was neuregulin-1 (NRG1). Administration of NRG1 protected naïve (non-atopic) mice from death with both SeV and mouse adapted influenza A virus (IAV). Survival was associated with reduced alveolar epithelium permeability and reduced phosphorylation of mixed lineage kinase domain-like (MLKL) protein indicating inhibition of necroptosis. In vitro, treatment of mouse lung epithelial cells with NRG1 inhibited SeV induced necroptosis, and NRG1 administration to differentiated human bronchial epithelial cells infected with RSV reduced transepithelial fluid leak and expression of necroptosis associated genes RIPK3 and MLKL, while regulating genes associated with homeostatic maintenance, suggesting stabilized epithelial integrity. In conclusion, our data demonstrate a unique function of NRG1 in respiratory viral infections by reducing alveolar leak, inhibiting epithelial necroptosis, and promoting homeostatic regulation of airway epithelium, all of which associate with markedly reduced mortality to the respiratory viral insult.
Insights
Neuregulin-1 (NRG1) protects against lethal respiratory viral infections by stabilizing lung epithelial integrity and inhibiting cell death. This discovery offers a potential therapeutic target for severe respiratory illnesses like RSV and influenza.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Respiratory infections caused by RNA viruses like respiratory syncytial virus (RSV) and influenza result in substantial illness and death.
- Atopic mice, sensitized with house dust mite, exhibited increased survival against a typically lethal Sendai virus (SeV) infection.
Purpose of the Study:
- To investigate the protective role of neuregulin-1 (NRG1) in respiratory viral infections.
- To determine the mechanisms by which NRG1 confers protection against viral-induced lung injury and mortality.
Main Methods:
- Utilized a Sendai virus (SeV) mouse model and influenza A virus (IAV) infection model.
- Administered NRG1 to atopic and naive mice, assessing survival rates and physiological parameters.
- Conducted in vitro studies on mouse lung epithelial cells and human bronchial epithelial cells infected with SeV or RSV, respectively, to examine necroptosis and epithelial barrier function.
Main Results:
- NRG1 was found to be elevated in atopic mice infected with SeV.
- NRG1 administration protected mice from lethal SeV and IAV infections, reducing alveolar epithelial permeability and inhibiting necroptosis (indicated by reduced MLKL phosphorylation).
- In vitro, NRG1 inhibited SeV-induced necroptosis in mouse lung cells and reduced RSV-induced fluid leak and necroptosis gene expression (RIPK3, MLKL) in human bronchial cells, promoting epithelial integrity.
Conclusions:
- Neuregulin-1 (NRG1) plays a critical role in mitigating respiratory viral infections.
- NRG1 functions by reducing alveolar leak, inhibiting epithelial necroptosis, and promoting airway epithelial homeostasis.
- These protective effects of NRG1 are associated with significantly reduced mortality following respiratory viral insults, suggesting its therapeutic potential.
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