Japanese encephalitis virus restricts HMGB1 expression to maintain MAPK pathway activation for viral replication

Japanese encephalitis virus (JEV) is a typical insect-borne flavivirus and an important zoonotic pathogen that causes human viral encephalitis and reproductive failure in pigs. Various strategies were utilized by JEV to facilitate its replication. It is important to identify key molecules that mediate JEV infection, as well as to investigate their underlying mechanism. In this study, the critical role of high-mobility group box 1 (HMGB1), a non-histone, DNA-binding protein, was assessed in JEV propagation. Upon JEV infection, the HMGB1 mRNA and protein levels were down-regulated at late infection in Huh7 cells. JEV replication was significantly enhanced with HMGB1 knock-down by siRNA and knock-out by the CRISPR/Cas9 system, whereas JEV growth was restricted in HMGB1-over-expressed Huh7 cells. Further investigation showed that HMGB1 suppressed MAPK pathway, and demonstrated that the weakening of MAPK pathway negatively regulated JEV infection. Together, these results suggested that JEV restricted HMGB1 expression to maintain MAPK pathway activation for viral replication. Our data showed that HMGB1 played a key role in JEV infection, providing the potential for the development of a novel drug to combat JEV infection.