The dysregulation of autophagy and ER stress induced by HHV-6A infection activates pro-inflammatory pathways and promotes the release of inflammatory cytokines and cathepsin S by CNS cells

•HHV-6A-mediated ER stress increases IL-1β, IL-6 and CXCL13 production by astrocytoma cells.•HHV-6A infection activates STAT3, NFkB and mTOR in astrocytoma cells.•HHV-6A promotes the cathepsin S release by astrocytoma cells and primary neurons.•4-PBA and DMF counteract all effects induced by HHV-6A infection. HHV-6A is a neurotropic herpesvirus able to infect several CNS cells including astrocytes and primary neurons. Here we found that HHV-6A infection of astrocytoma cells, by reducing autophagy, increased ROS and induced ER stress, promoting the release of inflammatory cytokines such as IL-6 and IL-1β and activating pathways such as STAT3, NF-kB and mTOR. Moreover, HHV-6A infection increased the production of CXCL13, a B lymphocyte attracting chemokine, whose recruitment in the CNS could further enhance neuroinflammation. Interestingly, HHV-6A also increased the release of cathepsin S by infected astrocytoma cells as well as by primary neurons. As this enzyme is involved in the degradation of MBP, this effect could contribute to the onset/progression of MS, a neurodegenerative disease that, besides inflammation, is characterized by a progressive demyelination process. In conclusion, this study unveils new molecular mechanisms through which HHV-6A may promote important aspects involved in several neurodegenerative diseases.