Fine-tuning of intracellular redox state by pro-glutathione molecules modulates the cellular immune/inflammatory response to infections: in vivo and in vitro studies.

The study was aimed to modulate intracellular redox-sensitive pathways to hinder directly the pathogen (like in the case of Mycobacterium avium), whose survival depends on the thiol-based redox metabolism which is fundamental to maintain a reducing environment to preserve cellular homeostasis, especially from ROS, and antibiotics, and indirectly by modulating the host’s immune/inflammatory response to the pathogen. Furthermore, it was investigated whether the redox state could play a role in immune/antiviral response by modulating folding and secretion of immunoglobulins. Alteration of redox state was induced by I-152 whose pro-GSH capacity had already been demonstrated, but the metabolism and the mechanism by which it increases intracellular GSH levels had not been studied in depth. In this thesis, one of the aims was also to deepen this aspect. Different redox-regulated pathways are involved in host responses towards several pathogens and alteration in redox balance, often characterized by GSH depletion, represents an exquisite strategy to evade or circumvent host innate immunity. These alterations can lead often to ineffective or exaggerated immune responses, which hamper the resolution of infections and are detrimental for the host. The data shown in this thesis suggest that the shift of the intracellular redox state towards a more reduced one could be a valid approach to influence and/or re-establish a balanced immune response and to interfere with the thiol-based redox metabolism which has a key role in vital processes for many pathogenic bacteria. Moreover, we can suggest that the idea of redox homeostasis involved in the management of oxidative stress is restrictive, and it should be considered as a fundamental metabolic and regulator key factor involved in several cellular functions, included the immune-associated ones.