Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling

Lukasz Kedzierski; Michelle D Tate; Alan C Hsu; Tatiana B Kolesnik; Edmond M Linossi; Laura Dagley; Zhaoguang Dong; Sarah Freeman; Giuseppe Infusini; Malcolm R Starkey; Nicola L Bird; Simon M Chatfield; Jeffrey J Babon; Nicholas Huntington; Gabrielle Belz; Andrew Webb; Peter Ab Wark; Nicos A Nicola; Jianqing Xu; Katherine Kedzierska; Philip M Hansbro; Sandra E Nicholson

doi:10.7554/eLife.20444

Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling

Elife. 2017 Feb 14:6:e20444. doi: 10.7554/eLife.20444.

Authors

Lukasz Kedzierski^{1

2}, Michelle D Tate^{3

4}, Alan C Hsu⁵, Tatiana B Kolesnik^{1

2}, Edmond M Linossi^{1

2}, Laura Dagley^{1

2}, Zhaoguang Dong⁶, Sarah Freeman^{1

2}, Giuseppe Infusini^{1

2}, Malcolm R Starkey⁵, Nicola L Bird⁷, Simon M Chatfield^{1

2}, Jeffrey J Babon^{1

2}, Nicholas Huntington^{1

2}, Gabrielle Belz^{1

2}, Andrew Webb^{1

2}, Peter Ab Wark⁵, Nicos A Nicola^{1

2}, Jianqing Xu⁶, Katherine Kedzierska⁷, Philip M Hansbro⁵, Sandra E Nicholson^{1

2}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
² Department of Medical Biology, University of Melbourne, Parkville, Australia.
³ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia.
⁴ Monash University, Clayton, Australia.
⁵ Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia.
⁶ Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁷ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Australia.

Abstract

Influenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.

Keywords: COPD; EGFR; PI3K; SOCS5; cell biology; human; infectious disease; influenza; innate immunity; microbiology; mouse; virus.

MeSH terms

Animals
Body Weight
Cytokines / metabolism*
Disease Models, Animal
ErbB Receptors / antagonists & inhibitors*
Humans
Influenza A virus / immunology*
Mice
Mice, Knockout
Orthomyxoviridae Infections / pathology
Orthomyxoviridae Infections / virology
Signal Transduction*
Suppressor of Cytokine Signaling Proteins / deficiency
Suppressor of Cytokine Signaling Proteins / metabolism*
Viral Load

Substances

Cytokines
SOCS5 protein, human
Socs5 protein, mouse
Suppressor of Cytokine Signaling Proteins
EGFR protein, human
EGFR protein, mouse
ErbB Receptors

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.