Researchers affiliated with the NIHR Sheffield Biomedical Research Centre have been awarded £7.5M in funding from the UK’s Advanced Research & Invention Agency (ARIA) to develop innovative approaches to protect against respiratory viruses, including influenza, COVID-19 and future pandemic threats.

The project, ASPIRE (anti-sense mediated state programming for respiratory epithelial defence), is led by Professor Thushan de Silva at the University of Sheffield. The multidisciplinary team includes collaborators from the University of Sheffield, Boston Children’s Hospital and Radboud University.

Enhancing the Body’s Innate Defence

The research focuses on the epithelial cells lining the respiratory tract, which form the body’s first line of defence against inhaled viruses. These airway cells play a critical role in determining how infections establish and progress. Notably, some cells naturally demonstrate increased resistance to viral infection, highlighting an opportunity to enhance these intrinsic protective mechanisms.

The ASPIRE programme aims to reprogramme airway epithelial cells into a protective antiviral state. Rather than continuously activating immune responses, the approach seeks to maintain cells in a poised condition - remaining inactive under normal conditions but able to respond rapidly upon viral exposure.

This state of readiness is regulated at the level of chromatin, which acts as a form of cellular memory. Central to this process are long non-coding RNAs (lncRNAs), which help establish and maintain these protective states.

Targeting Cellular Memory to Prevent Infection

Using advanced single-cell analysis of human nasal tissue samples and building on detailed cellular atlases of the airway, the team will identify protective epithelial cell states and the lncRNAs that underpin them.

The researchers will then design antisense oligonucleotides (ASOs) - short, targeted molecules that can selectively modify lncRNA function. By altering these regulatory pathways, the aim is to reset cellular memory so that antiviral protection persists even after the therapeutic intervention has been cleared.

This work will provide proof of concept for a new class of medicines known as sustained innate immunoprophylactics (SIIPs), designed to deliver durable, broad-spectrum antiviral protection by harnessing innate immune mechanisms.

Towards Long-Lasting, Broad-Spectrum Protection

In the longer term, this research could enable the development of an “off-the-shelf” nasal spray capable of providing months-long protection against a wide range of respiratory viruses from a single course of treatment.

The ASPIRE project forms part of ARIA’s wider Sustained Viral Resilience programme, which is supporting 11 international teams to develop next-generation strategies that go beyond traditional vaccine approaches by offering broader and longer-lasting protection.

The NIHR funds, enables and delivers world-leading health and social care research that improves people's health and wellbeing and promotes economic growth.

NIHR Biomedical Research Centres (BRCs) are collaborations between NHS organisations and universities. They bring together academics and clinicians to translate scientific discoveries into potential new treatments, diagnostics and technologies.