Ricerc@Sapienza

Invading viruses are sensed by PRRs that trigger an intracellular signaling culminating in the release of anti-viral, pro-inflammatory and anti-inflammatory cytokines. Besides triggering PRR signaling, viral infection perturbs ER homeostasis and activates UPR, a stress response orchestrated by three main sensors, namely IRE1alpha PERK and ATF6. They regulate the activation of several downstream molecules, leading to adaption to cell stress unless the stress is too strong and the adaptive response overwhelmed. Besides this, UPR intersects with PRR signaling controlling the amount and the type of cytokine released, regulating inflammation and shaping immune response. Several cytokines, once released, may re-activate UPR, in a positive feed-back loop that prolongs or exacerbates the inflammatory response. Although aimed at defending the host from pathogens, if too strong or long lasting, inflammation may result in acute tissue damage or become chronic, leading to tissue remodelling. In some patients infected by acute respiratory viruses or in which herpesviruses reactivate due to immune deficiency, a cytokine storm may be released, destroying alveolar epithelial cells and causing the acute respiratory distress syndrome (ARDS), to which contribute endothelial cell damage, the activation of the coagulation cascade and the stimulation of fibroblast trans-differentiation and fibrosis. In the case of prolonged inflammation, virus infection or reactivation induces tissue remodelling and predisposes to a variety of diseases from neurodegeneration to cancer. Based on this knowledge, in this proposal we aim to investigate whether the manipulation of UPR and PRR signaling in epithelial, endothelial and immune cells infected by respiratory viruses such as influenza or herpesviruses or in bystander uninfected cells could regulate the cytokine release, restore immune response and reduce inflammation, preventing tissue damage and the cosequences of inflammation chronicity .