AMPK activation by hepatitis E virus infection inhibits viral replication through attenuation of autophagosomes and promotion of innate immunity.

Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. The mechanisms orchestrating such an infection course remain to be elucidated. AMP-activated protein kinase (AMPK) is a pivotal cellular sensor for maintaining metabolic homeostasis. Here, we show that AMPK is activated in response to HEV infection and is associated with mitochondrial damage and ATP deficiency. AMPK activation, in turn, inhibits HEV replication. Mechanistic studies reveal that AMPK activation triggers the expression of interferon (IFN)-stimulated genes that possess antiviral properties. In parallel, AMPK inhibits autophagosome accumulation to exert antiviral effects. Interestingly, AMPK activation also suppresses the inflammatory response triggered by HEV infection. Consistently, AMPK activation simultaneously exerts anti-inflammatory and antiviral effects in a coculture system of HEV-infected liver cells with macrophages. These findings pave the way for the development of AMPK-targeted therapeutics to treat hepatitis E.