Interfering with transmission

The IFNλ family of interferons controls the spread of viruses in the upper respiratory tract and transmission between mice.

T he evolutionary arms race between viruses and their vertebrate hosts is biased by the different rates at which each can adapt. Slowly evolving vertebrate genomes cannot keep up with the rapid mutations employed by viral genomes to avoid the host's defenses. One strategy that vertebrates use to counter this apparent disadvantage involves a group of proteins called interferons that infected cells produce when they sense a virus. Named for their ability to 'interfere' with influenza virus replication (Isaacs and Lindenmann, 1957), interferons switch on a battery of hundreds of genes, many of which encode antiviral proteins (Mostafavi et al., 2016).
Interferons can be classed into different families, each of which interacts with a different receptor. The most widely studied family is the IFNab family, which interacts with the IFNab receptor (McNab et al., 2015). The IFNl family of interferons, which interact with the IFNl receptor, were discovered more recently . Now, in eLife, Peter Staeheli of the University of Freiburg and co-workers -including Jonas Klinkhammer and Daniel Schnepf as joint first authors -report a unique role for IFNl in virus transmission (Klinkhammer et al., 2018).
IFNab and IFNl activate largely the same genes, but their receptors are not found on all cell types. Therefore, the distribution of IFNab and IFNl receptors could be behind the different biological effects of each interferon family. Epithelia are thought to express both receptors, and therefore the two interferon families should both have the same effects in the epithelial cells that line the surfaces of organs, including the airways. A number of findings support this. First, the influenza virus triggers the airway epithelia of mice lacking one type of receptor to transcribe practically the same sets of genes as those transcribed in the epithelia of normal mice: however, epithelia that lack both interferon receptors have large 'holes' in their transcriptional profile and allow the virus to replicate extensively (Crotta et al., 2013). Second, mice that are deficient in one type of receptor experience a mild increase in their risk of developing disease when infected, whereas mice that lack both types are far more severely afflicted (Mordstein et al., 2008).
To show that IFNl has unique roles in epithelial cells Klinkhammer et al. -who are based at Freiburg, Aarhus University and the University of Geneva -infected mice with a strain of influenza virus in a small volume of fluid. This mimics the ways that infections spread between humans better than the larger volumes of fluid used in most studies. Using this technique, infection was initially limited to the epithelia lining the nasopharyngeal cavities.
IFNl receptor-deficient mice infected in this way had a far greater number of virus particles in their upper airways than mice that were deficient in the IFNab receptor. This suggests that nasopharyngeal epithelia may be more responsive as a whole to IFNl than to IFNab, or that some cells in these epithelia express only the IFNl receptor. However, IFNab receptors become increasingly important when mice are infected with larger droplets, which brings the virus further down into the lungs, or during an ongoing infection if the virus succeeds in spreading further down along the airways into the lung.
The efficiency with which viruses are transmitted from infected to uninfected individuals makes the difference between minor outbreaks (such as sporadic cases of H5N1) and pandemics (such as the H1N1 pandemic of 2009). A lack of a genetically versatile animal model had made it difficult to study how the genome of the host affects transmission frequency, but this changed when it was shown that H3N2 influenza viruses transmit efficiently between mice (Edenborough et al., 2012).
Using this model Klinkhammer et al. show that IFNl determines transmission efficiency by controlling the number of virus particles at the uppermost end of the respiratory tract: the higher the number of viruses in the nasopharyngeal space, the higher the likelihood that they would be shed out of the nose and thus be able to infect a new host. In line with its role further down the respiratory tract, IFNab has much less influence on how well the virus spreads between individuals.
The results also have clinical relevance. Klinkhammer et al. demonstrate here that IFNl acts more strongly than IFNab and has longer-lasting effects on virus transmission, while others have shown that it also produces comparably minor inflammatory side effects (Davidson et al., 2016;Galani et al., 2017). Treatment with an IFNl spray may therefore benefit patients with influenza, as well as anyone they encounter during their illness.
There had been previous indications that IFNl has a unique role in controlling infections. Last year it was reported that IFNl appeared to be the first interferon, and sometimes the only interferon, required to control the influenza virus early in infections and when using low doses of the virus (Galani et al., 2017). There also seems to be a parallel situation in the small intestine where IFNl, and not IFNab, determines the outcome of some viral infections (Mahlakõ iv et al., 2015;Pott et al., 2011;Figure 1). Furthermore, at both sites, some epithelial cells appear to respond only to IFNl. What are these cells? Are there more sites in the body where this response pattern is found? Do these cells express a unique pattern of receptors, or is their response determined by other mechanisms? Like all important studies, the work presented by Klinkhammer et al. answers some questions while also raising many others.