MON-623 - Metformin as a Host-Directed Therapy to Modulate Inflammation and Improve Outcomes in Viral Infection

Viral pneumonia is a major cause of morbidity and mortality. Metformin has emerged as a potential therapy for respiratory viral infections, with observational human data suggesting improved outcomes in infected diabetic patients and prospective studies in non-diabetic populations. However, the mechanisms and cellular compartments mediating this protective effect remain unclear. We have developed a clinically relevant model to investigate the impact of metformin on influenza infection. Importantly, lean mice treated with oral metformin for 5 days starting 3 days post infection to mimic acute clinical treatment show improved clinical outcomes, including reduced weight loss and improved oxygen saturation compared to controls. As metformin has been reported to target mitochondrial complex I and mitochondrial metabolism is known to regulate immunity, we evaluated whether this pathway contributes to the observed effect. Transgenic mice conditionally expressing a yeast complex I analog, NDI1, specifically in hematopoietic cells showed reduced responsiveness to metformin, with these animals displaying increased weight loss and lower oxygen saturation during influenza infection. These findings indicate that metformin confers protection during influenza infection through modulation of mitochondrial complex I in immune cells. This supports a model in which metabolic reprogramming influences inflammatory outcomes and disease severity and provides a mechanistic basis for the clinical benefit observed with metformin in viral infections. Ongoing studies aim to define the specific immunologic compartment responsible for mediating these effects to support therapeutic repurposing and enable more targeted treatment strategies.

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