Celastrol can alleviate severe influenza by inhibiting NETs

What is it about?

Severe influenza virus infections, often exacerbated by delayed antiviral treatment, remain a significant global health challenge, contributing to high rates of morbidity and mortality. Current therapeutic approaches generally combine antiviral agents with anti-inflammatory strategies. However, the use of glucocorticoids, a common class of immunomodulators, remains contentious due to the associated risk of secondary infections, highlighting the urgent need for safer and more targeted anti-inflammatory therapies.To identify safer and more targeted anti-inflammatory therapies for severe influenza virus infections and evaluate their efficacy in combination with antiviral agents through innovative computational and experimental approaches. We developed a novel pipeline based on machine learning algorithm for the identification of anti-inflammatory drug candidates. Using this approach, we screened and identified celastrol as a promising therapeutic agent. We then combined celastrol with baloxavir in a murine model of severe influenza virus infection to assess survival outcomes. Mechanistic studies were performed to investigate the molecular targets and effects of celastrol, particularly its impact on Clcn3 and neutrophil extracellular traps (NETs) formation.

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Photo by Chinh Le Duc on Unsplash

Photo by Chinh Le Duc on Unsplash

Why is it important?

Our findings revealed that the combination of celastrol and baloxavir significantly enhanced survival rates in the murine model of severe influenza infection. Mechanistic analyses indicated that celastrol may target Clcn3, which directly inhibits NETs formation, thereby reducing vascular damage and improving clinical outcomes. These results demonstrate the potential of celastrol as a therapeutic agent for severe influenza virus infections. This study introduces a robust machine learning-based framework for anti-inflammatory drug discovery in the context of influenza virus infection and identifies celastrol as a potential candidate for combination therapy with baloxavir. The findings not only have implications for enhancing influenza treatment but also provide a foundation for the development of targeted anti-inflammatory therapies for other severe viral infections.

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