X-linked Chronic Granulomatosis: molecular and cellular mechanisms underlying intestinal inflammation

X-linked Chronic Granulomatous Disease (CGD, OMIM 306400) is a rare primary immunodeficiency caused by defects in the CYBB gene, encoding the gp91phox subunit (Nox2) of the NADPH oxidase complex. The oxidase catalyzes the production of reactive oxygen species, which are critical to the killing of phagocytosed pathogens. Affected individuals typically develop life-threatening infections, as well as unexplained autoinflammatory/autoimmune conditions, involving particularly the intestine. The management of CGD is limited by the serious side effects of the high doses of the available therapies. Hematopoietic stem cell transplantation represents a definitive cure for patients with a suitable matched donor; gene therapy represents an alternative promising approach. Recent data indicate that different cell type may be responsible for the abnormal responses of the immune system in the disease setting, suggesting that unforeseen immunoregulatory and functional properties might likewise be affected by the Nox2-deficiency. This project will investigate the cellular and molecular bases of intestinal inflammation in X-CGD. The contribution of Nox2 in the phagocytic and lymphocyte-mediated control of intestinal homeostasis will be dissected in mouse models and patients’ samples and in relation to the resident gut microbiota. Results will ensure a better understanding of the disease pathogenesis. Furthermore, they could lead to the redefinition of therapeutic targets and optimization of curative strategies.