TLR-2-mediated activation of innate responses in the upper airways confers anti-viral protection of the lungs

Georgia Deliyannis; Chinn Yi Wong; Hayley A. McQuilten; Annabell Bachem; Michele V. Clarke; Xiaoxiao Jia; Kylie Horrocks; Weiguang Zeng; Jason Girkin; Nichollas E. Scott; Sarah L. Londrigan; Patrick C. Reading; Nathan W. Bartlett; Katherine Kedzierska; Lorena E. Brown; Francesca A. Mercuri; Christophe Demaison; David C. Jackson; Brendon Y. Chua

doi:10.1172/jci.insight.140267

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Deliyannis, G. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Wong, C. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by McQuilten, H. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Bachem, A. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Clarke, M. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Jia, X. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Horrocks, K. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Zeng, W. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Girkin, J. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Scott, N. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Londrigan, S. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Reading, P. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Bartlett, N. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Kedzierska, K. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Brown, L. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Mercuri, F. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Demaison, C. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Jackson, D. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

²Viral Immunology and Respiratory Disease Group, University of Newcastle, Newcastle, Australia

³Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

⁴Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia

⁵Ena Therapeutics Pty Ltd, Ena Therapeutics Pty Ltd, Melbourne, Australia

Find articles by Chua, B. in: JCI | PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.140267.
Copyright © 2021, Deliyannis et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published February 9, 2021 - Version history

The impact of respiratory virus infections on global health is felt not just during a pandemic but for many, endemic seasonal infections pose an equal and ongoing risk of severe disease. Moreover, vaccines and antiviral drugs are not always effective or available for many respiratory viruses. We investigated how induction of effective and appropriate antigen independent innate immunity in the upper airways can prevent spread of respiratory virus infection to the vulnerable lower airways. Activation of Toll-like receptor-2 (TLR2), when restricted to the nasal turbinates results in prompt induction of innate immune-driven anti-viral responses through action of cytokines, chemokines and cellular activity in the upper but not the lower airways. We define how nasal epithelial cells and recruitment of macrophages work in concert and play pivotal roles to limit progression of influenza virus to the lungs and sustain protection for up to seven days. These results reveal underlying mechanisms of how control of viral infection in the upper airways can occur and also support the implementation of strategies that can activate TLR2 in nasal passages to provide rapid protection, especially for at-risk populations, against severe respiratory infection when vaccines and antiviral drugs are not always effective or available.

Version 1 (February 9, 2021): In-Press Preview

TLR-2-mediated activation of innate responses in the upper airways confers anti-viral protection of the lungs

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