The role of the tissue-damage signaling protein HMGB1 in cytomegalovirus infection

Abstract

High mobility group box 1 (HMGB1) protein is a highly multifunctional and abundant molecule known for its engagement in various DNA-associated processes and for its role as a damage-associated molecular pattern (DAMP). Initially concentrated in the cell nucleus, HMGB1 can translocate into the cytoplasm and be released into the extracellular milieu by active secretion, cell death or tissue injury. Extracellular HMGB1 is a potent signaling molecule regulating numerous inflammatory processes in the context of sterile tissue damage as well as infections. However, the impact of HMGB1-mediated signaling on pathogen defense and viral clearance remains poorly understood. Recent research suggests that HMGB1 has versatile functions. Indeed, it could support viral replication when present intracellularly but it is also known to restrict viral spread especially when it is released into the extracellular space. However, most studies focus on RNA viruses, while knowledge about the influence of HMGB1 on the life cycle and spread of DNA viruses is remarkably small. Since HMGB1 can exert diverse and opposing functions, the aim of this study is to further investigate the role of HMGB1 during infection with a DNA virus, the cytomegalovirus (CMV), and to evaluate its contribution to viral progression and/or elimination. In order to investigate the impact of HMGB1 on CMV replication, the well-established mouse CMV (MCMV) infection model is used alongside transgenic HMGB1-deficient mice and murine cell cultures with altered HMGB1 expression. The results obtained in the present study indicate that HMGB1 supports early MCMV transcription and is highly likely to interact with viral genomes, as it remains in the nucleus of infected cells and locates to viral replication compartments. In contrast, the data shows that extracellular HMGB1 released by MCMV-infected cells inhibits viral replication in a cell type-dependent manner. In macrophages in particular, virustriggered release of HMGB1 induces cell death, which limits viral growth in these cells. In agreement with these in vitro results, HMGB1 was shown to support early MCMV replication in vivo. However, at later stages of infection, the presence of HMGB1 seems to negatively affect viral replication and/or dissemination.