Phd in EXPERIMENTAL MEDICINE

Thesis title: HHV-6 DYSREGULATES AUTOPHAGY AND UPR IN THE INFECTED CELLS: IMPACT ON IMMUNE RESPOSE AND NEURODEGENERATIVE DISEASE

HHV-6A and HHV-6B are herpesviruses characterized by high level of homology, both isolated for the first time from immune-suppressed patients but able to infect different target cells. HHV-6B is the causative agent of exanthema subitum, a self-limiting disease that arises in young children, while no diseases have been shown to be caused by HHV-6A primary infection. These viruses are known to induce immune suppression and share the characteristic to be neurotropic, even if HHV6-A more efficiently replicate in neuronal cells compare to HHV-6B. However, HHV-6A and B have been associated with central nervous system (CNS) diseases, particularly a high number of HHV-6A viral copies have been found in the brains of patients suffering of Alzheimer’s disease (AD). Autophagy is a cellular process involved in several physiologic processes including immune response and CNS homeostasis. Although mostly of viruses, including Herpesviruses, have been shown to subvert autophagy to their own advantage, this PhD project reports for the first time that HHV-6A and HHV-6B are able to manipulate autophagy in the cells in which they replicate, and more importantly in monocytes in which this effect and the consequent ER stress induction prevents their differentiation into dendritic cells. Viral infection, in addition to ER stress, increased the level of intracellular ROS and activated STAT1 and STAT3 pathway, up-regulating PD-L1, to further induce immune dysfunction and favoring viral escape from immune recognition. Another consequence of autophagy dysregulation and ER stress/UPR induction by HHV-6A infection was the A accumulation and Tau protein hyperphosphorylation in astrocytes and primary neurons, which support a possible association of HHV-6A with AD. In conclusion this study evidences for that HHV-6A and HHV-6B infection has a strong impact on autophagy and ER stress/UPR in different cell types and that through this effect these viruses promote immune dysfunction and diseases.