In a groundbreaking study published in the journal Nature, scientists from Tufts University School of Medicine and collaborating institutions have discovered a promising new compound capable of reversing the course of influenza infection in mice. By blocking a cell death response called necroptosis, the compound, known as UH15-38, effectively prevents life-threatening injury to lung tissue.

Current treatment options for serious flu infections are limited to symptom management until the body can combat the virus on its own. However, previous evidence has shown that influenza-induced necroptosis can cause lung injury, prompting researchers to explore methods of inhibiting this process. The team demonstrated that UH15-38 can effectively and safely block the key receptor responsible for necroptosis in lung cells, reducing inflammation and protecting the host from damage.

Associate Professor Alexei Degterev, co-corresponding author of the study, explained, "If you remove necroptosis, you still get restriction of viral replication without causing massive damage to the lungs. Necroptosis does not appear to be necessary for restricting viral activity, so if we can block it, we will be able to protect the host by reducing inflammation in the lungs."

Necroptosis is triggered when a cell under duress activates its receptor interacting protein kinase 3 (RIPK3) pathway, which attracts immune cells to the affected area. UH15-38 inhibits the activation of RIPK3 pathway, thereby reducing excessive inflammation. Importantly, the compound was well-tolerated in mice, preventing any influenza-related deaths even when administered up to five days into the infection.

The potential of compounds like UH15-38 to address severe flu infections and other viruses that trigger respiratory symptoms is significant. By targeting the inflammation that is intended to be protective but can cause harm, these compounds offer a new approach to treatment.

Degterev emphasized the importance of this research beyond the current COVID-19 pandemic, stating, "While the worst of COVID-19 may be behind us, the credible expectation is that there will be another pandemic. We need something that is going to protect the host independent of how the host is infected. This work highlights the possibility of achieving such a goal and renews interest in how cell death shapes infections."

The study's success was made possible through the collaboration of researchers from multiple institutions, including Fox Chase Cancer Center, the University of Houston, and St. Jude Children's Research Hospital. Tufts University played a crucial role in organizing the study and providing key insights into the UH15-38 inhibitor.

Moving forward, Degterev and his colleagues are working on the second generation of these inhibitors and exploring their potential in protecting against other respiratory diseases. The commercialization of UH15-38 is being managed by Tufts University's Office for Technology Transfer and Industry Collaboration.

As this research progresses into further preclinical and human trials, the development of compounds like UH15-38 could revolutionize flu treatment by providing a new way to combat severe infections. By selectively blocking necroptosis, these compounds have the potential to protect lung tissue and improve outcomes for patients.

Reference:
Siddharth Balachandran, Necroptosis blockade prevents lung injury in severe influenza, Nature (2024). DOI: 10.1038/s41586-024-07265-8. www.nature.com/articles/s41586-024-07265-8