IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission

  1. Jonas Klinkhammer
  2. Daniel Schnepf
  3. Liang Ye
  4. Marilena Schwaderlapp
  5. Hans Henrik Gad
  6. Rune Hartmann
  7. Dominique Garcin
  8. Tanel Mahlakõiv
  9. Peter Staeheli  Is a corresponding author
  1. Medical Center University of Freiburg, Germany
  2. Aarhus University, Denmark
  3. University of Geneva, Switzerland

Abstract

Host factors restricting the transmission of respiratory viruses are poorly characterized. We analyzed the contribution of type I and type III interferon (IFN) using a mouse model in which the virus is selectively administered to the upper airways, mimicking a natural respiratory virus infection. Mice lacking functional IFN-λ receptors (Ifnlr1-/-) no longer restricted virus dissemination from the upper airways to the lungs. Ifnlr1-/- mice shed significantly more infectious virus particles via the nostrils and transmitted the virus much more efficiently to naïve contacts compared with wild-type mice or mice lacking functional type I IFN receptors. Prophylactic treatment with IFN-α or IFN-λ inhibited initial virus replication in all parts of the respiratory tract, but only IFN-λ conferred long-lasting antiviral protection in the upper airways and blocked virus transmission. Thus, IFN-λ has a decisive and non-redundant function in the upper airways that greatly limits transmission of respiratory viruses to naïve contacts.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Jonas Klinkhammer

    Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel Schnepf

    Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Liang Ye

    Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Marilena Schwaderlapp

    Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Hans Henrik Gad

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8449-1115
  6. Rune Hartmann

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Dominique Garcin

    Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1556-897X
  8. Tanel Mahlakõiv

    Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Peter Staeheli

    Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
    For correspondence
    peter.staeheli@uniklinik-freiburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7057-6177

Funding

Deutsche Forschungsgemeinschaft

  • Peter Staeheli

Novo Nordisk

  • Rune Hartmann

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

  • Dominique Garcin

European Commission

  • Peter Staeheli

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

Ethics

Animal experimentation: Animals were handled in accordance with guidelines of the Federation for Laboratory Animal Science Associations and the national animal welfare body. Animal experiments were performed in compliance with the German animal protection laws and were approved by the university's animal welfare committee (Regierungspräsidium Freiburg; permit G-15/59).

Copyright

© 2018, Klinkhammer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,665
    views
  • 948
    downloads
  • 208
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jonas Klinkhammer
  2. Daniel Schnepf
  3. Liang Ye
  4. Marilena Schwaderlapp
  5. Hans Henrik Gad
  6. Rune Hartmann
  7. Dominique Garcin
  8. Tanel Mahlakõiv
  9. Peter Staeheli
(2018)
IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission
eLife 7:e33354.
https://doi.org/10.7554/eLife.33354

Share this article

https://doi.org/10.7554/eLife.33354

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Malika Hale, Kennidy K Takehara ... Marion Pepper
    Research Article

    Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

    1. Cell Biology
    2. Immunology and Inflammation
    Alejandro Rosell, Agata Adelajda Krygowska ... Esther Castellano Sanchez
    Research Article

    Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.