Respiratory viruses such as RSV are a leading cause of illness in young children, older adults, and immunocompromised individuals, with limited treatment options available. Researchers from COI (Dr Jiyeon Ha, Prof Jane McKeating and Dr Peter Wing), University of Liverpool (Prof James Stewart) and University of Zurich (Prof Anja Kipar) have identified a promising new strategy to enhance the body’s natural immune response to respiratory viruses, including respiratory syncytial virus (RSV), a major cause of severe lung infections. In a study published in Proceedings of the National Academy of Sciences (PNAS), the team showed that activating a key oxygen-sensing pathway in cells-known as the hypoxia-inducible factor (HIF) pathway can significantly limit viral replication and improve antiviral immunity.
Reprograming the immune response
The researchers used Daprodustat, a clinically approved drug, to activate the HIF pathway. They found that this treatment enhanced the body’s innate immune response, the first line of defence against viral infection, by boosting the expression of antiviral genes and interferon signalling. Crucially, the study revealed that this effect depends on the body’s ability to detect viral genetic material. When key viral sensing pathways were blocked, the protective effect of HIF activation was lost, highlighting the importance of early immune detection.
Making viruses more visible
The team also uncovered a previously unrecognised mechanism by which HIF improves immune defence. Central to this process is a chemical modification of RNA known as N6-methyladenosine (m⁶A), which is commonly added to viral RNA and can help viruses evade immune recognition. The researchers found that activation of the HIF pathway promotes ‘eraser proteins’ that remove m⁶A modifications on RSV RNA. This reduction in m⁶A modifications resulted in the viral genome being more readily detectable by cellular RNA sensors, such as RIG-I-like receptors, which are responsible for triggering antiviral interferon responses. By stripping away a layer of molecular camouflage, HIF activation enhances the ability of host cells to recognise the virus and mount a rapid immune response. This discovery highlights a new link between cellular metabolism, RNA modification, and antiviral defence.
Towards new treatments
Respiratory syncytial virus remains a leading cause of hospitalisation worldwide, particularly in young children, with limited treatment options available. The findings suggest that repurposing existing drugs that target the HIF pathway could offer a new therapeutic approach. The study provides fresh insight into how oxygen-sensing pathways interact with antiviral immunity and opens new avenues for the development of treatments against respiratory viral infections.
Read about the study here.