Media release

From: Springer Nature

Medicine: Preventing lung injury associated with influenza in mice (N&V)

A new drug candidate shown to lessen the lung damage and improve survival rates associated with influenza A infection in mice is demonstrated in a study published in Nature. This agent has the potential to benefit a wide range of inflammatory conditions and offers new insights into the pathways associated with inflammatory disease.

Severe cases of influenza A, which are responsible for up to 650,000 deaths globally per year, can cause hyper-inflammation, lung injury and acute respiratory distress syndrome. As a defence mechanism, the presence of influenza particles can activate a process called apoptosis, by which select cells are purposefully culled to limit viral spread. This occurs via the activation of an enzyme named RIPK3. However, during infection this enzyme can activate another closely related pathway, which can then cause uncontrolled cell death (necroptosis) and exacerbate the inflammation and lethality caused by influenza. Inhibitors of RIPK3 are a popular drug target, but a stable candidate that can block one pathway and not the other is yet to be identified.

Siddharth Balachandran and colleagues have developed a drug named UH15-38, a potent RIPK3 inhibitor that is able to block necroptosis in cell lines without affecting the apoptosis signalling pathway. Tests in mice identified the ideal dose that could reduce and delay illness-induced weight loss, with these mice then making full recoveries by three weeks post-infection. UH15-38-treated mice also showed reduced inflammatory markers and necroptotic lung cells, indicating that the selective blockade of this pathway is beneficial in preventing the excessive inflammation and lung damage associated with influenza infection. Notably, UH15-38 was shown to be effective when administered up to five days after infection, suggesting that the positive effects of blocking this inflammation are felt even during peak viral replication.

These results demonstrate the potential for UH15-38 to provide substantial protection against severe inflammation and disease from influenza in mice. In addition, its success in selectively inhibiting RIPK3 (which is essential for the progression of necroptosis) suggests a potential to benefit a wide range of inflammatory conditions.