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

• Published in: eLife Vol. 7
• Main Authors: Klinkhammer, Jonas, Schnepf, Daniel, Ye, Liang, Schwaderlapp, Marilena, Gad, Hans Henrik, Hartmann, Rune, Garcin, Dominique, Mahlakõiv, Tanel, Staeheli, Peter
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 13.04.2018; eLife Sciences Publications, Ltd
• Subjects: Animals; Antiviral drugs; Disease transmission; Gene expression; Immunology and Inflammation; Infections; Influenza; Influenza virus; interferons; Medicine; Microbiology and Infectious Disease; Mimicry; Respiratory tract; transmission; Variance analysis; Viral infections; Viruses; α-Interferon; Denmark; United States > US; Freiburg Germany; Aarhus Denmark; Germany; mouse; interferons; transmission; Influenza virus; infectious disease; inflammation; respiratory tract; microbiology; immunology; virus
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.33354

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. Influenza (‘the flu’) and other respiratory viruses make millions of people ill every year, placing a large burden on the healthcare system and the economy. Unfortunately, few options for preventing or treating these infections currently exist. The flu virus spreads from infected individuals, enters a new host through the nose and establishes an infection in the upper airways. If the infection stays restricted to this region of the respiratory tract – which consists of the nasal cavity, sinuses, throat and larynx – it causes a rather mild disease. However, if it spreads to the lungs it can cause potentially life-threatening viral pneumonia. Epithelial cells line the upper respiratory tract, forming a physical border between the outside world and the human body. These cells are therefore the first to face the incoming virus. In response, the epithelial cells release messenger molecules termed interferons that warn nearby cells to increase their antiviral defenses. There are several subtypes of interferons, such as IFN-α, IFN-β and IFN-λ, but it was not known how each subtype helps to combat respiratory viruses. To investigate, Klinkhammer, Schnepf et al. exposed mice to flu viruses in a way that mimicked how an infection would naturally start in the upper airways in humans. Some of the mice were genetically engineered so that they could not respond to either IFN-α/β or IFN-λ. The virus spread most effectively from the nasal cavity to the lungs in mice whose IFN-λ system was defective. Infections in mice that lacked IFN-λ were also more likely to spread to other individuals. Furthermore, treating mice with IFN-λ, but not IFN-α, gave their upper respiratory tract long-lasting protection against flu infections and prevented the spread of the virus. IFN-λ therefore has a specific and significant role in protecting the upper airways against viruses, and could potentially be used as a drug to block the spread of infections between humans. Currently, IFN-λ is in clinical trials as a potential treatment for hepatitis D. To repurpose it for upper respiratory tract infections, its effectiveness against specific respiratory viruses will first have to be evaluated.