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