LA MODULAZIONE DEI LIVELLI DI GLUTATIONE COME STRATEGIA DI ATTACCO NELLE INTERAZIONI OSPITE-PARASSITA

Insect studies, dealing with parasitism of aphids, have shown that the disruption of host glutathione (GSH) pool and\udmetabolisms significantly contributes to its physiological regulation and castration. The parasitic wasp Aphidius ervi injects into\udhost aphids a venom containing large amounts of a gamma-glutamyltransferase (Ae-GGT) enzyme, which causes a depletion of\udGSH primarily involving ovarian tissue. Injected Ae-GGT in fact consumes substrate GSH, which ultimately triggers apoptosis.\udStudies on virulence factors of microrganisms have documented that the invasion strategies of selected pathogenic bacteria also\udtarget host GSH metabolism. Indeed, it has been shown that GGT activity of Helicobacter pylori and H. suis, the agents responsible\udof peptic ulcer, can exert antiproliferative and pro-apoptotic effects in gastric epithelial cells. By confocal microscopy, H. suis outer\udmembrane vesicles (OMV) − submicroscopic structures 20-50 nm in diameter, budding from the cell surface − were identified as\udcarriers of H. suis GGT, capable of delivering the enzyme to the deeper mucosal layers. In association with such membranous\udstructures, active GGT from H. suis in fact translocates across the epithelial layers and can access lymphocytes residing in the\udgastric mucosa, resulting in the inhibition of lymphocyte proliferation, i.e., a perturbation of host immunity and a facilitation of\udbacterial infection. Cellular GSH appears, thus, to represent a conserved target for parasitic (micro)organisms which aim at altering\udhost redox homeostasis to weaken its immune defenses, using GGT as a key-element of a virulence strategy. Taking into account\udthe “parasitic” behavior exhibited by malignant cells spreading across tissues and organs of the patient (the “host”). GGT activity\udis in fact expressed in a number of malignant tumors, and expression levels often increase along with progression to more invasive\udphenotypes. Now, active GGT can be released from cells, including cancer cells, in association with submicroscopic vesicles resembling\udexosomes. The similarity of such structures with GGT-rich OMV particles of H. pylori and H. suis is indeed obvious. GGT\udactivity of cancer cells can affect intracellular redox equilibrium, and produces in addition significant extracellular effects, e.g. on\udthe redox status and ligand binding affinity of cell surface receptors related with cell survival/apoptosis balance. Thus, GGT-rich\udexosomes shed by cancer cells can produce in host’s surrounding tissues effects comparable to those reported for Ae-GGT or Helicobacter\udGGT, possibly resulting in facilitation of malignant cells survival and diffusion