Metformin as antiviral therapy protects hyperglycemic and diabetic patients

ABSTRACT Viral infections disrupt glucose metabolism; however, their impact on disease prognosis in highly pathogenic viruses remains largely unknown. There is an additional need to investigate the antiviral mechanisms of glucose-lowering therapeutics. Here, our multicenter clinical study shows that hyperglycemia and pre-existing diabetes are independent risk factors for mortality in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging and highly pathogenic bunyavirus. SFTSV infection triggers gluconeogenesis, which, in turn, inhibits AMPK activity and subsequent interferon I (IFN-I) responses, thereby facilitating viral replication. In vitro and animal studies further reveal that metformin inhibits SFTSV replication by suppressing autophagy through the AMPK-mTOR pathway, contributing to protection against lethal SFTSV infection in mice. Importantly, our large cohort study demonstrates that metformin reduces viremia and SFTSV-related mortality in patients with hyperglycemia or pre-existing diabetes, contrasting with the disadvantageous effect of insulin. These findings highlight the promising therapeutic potential of metformin in treating viral infections, particularly among individuals with hyperglycemia or diabetes. IMPORTANCE Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne bunyavirus, causes severe hemorrhagic fever with a high mortality rate. Previous studies have shown metabolic disturbances, particularly hyperglycemia, in SFTSV-infected individuals. However, the mechanism underlying this metabolic derangement remains unclear, and further investigation is needed to determine whether glucose-lowering therapeutics could be beneficial for SFTSV-infected patients. In this study, our multicenter clinical data show that hyperglycemia and pre-existing diabetes are independent risk factors for mortality in patients with SFTSV infection. Furthermore, we observed that SFTSV infection triggers gluconeogenesis, which promotes viral replication through the regulation of the AMPK-IFN-I signaling pathway. Notably, metformin significantly reduces viremia and SFTSV-related mortality in patients with hyperglycemia or pre-existing diabetes, attributed to its inhibitory effect on autophagy through the AMPK-mTOR pathway. Therefore, our study uncovers the interaction between SFTSV infection and glucose metabolic disorder and highlights the promising therapeutic potential of metformin for treating SFTSV infection.