Reichenbach
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Immunologie, Abteilung » Prof. Dr. Reinhard Seger (emeritiert) » Reichenbach
Completed research project
| Title / Titel | Role of macroautophagy in chronic granulomatous disease (CGD) and correction of the defect | ||
|---|---|---|---|
| Abstract (PDF, 14 KB) | |||
| Summary / Zusammenfassung | CGD is a group of rare genetic immunodeficiencies (total incidence 1:70’000 newborns) caused by mutations in 3 cytosolic or 2 membrane-associated subunits of the NADPH oxidase. This results in defects in the respiratory burst necessary for destruction of ingested microorganisms, leading to severe recurrent bacterial and fungal infections of body surfaces and internal organs. We have previously shown that defective formation of neutrophil extracellular traps (NETs) is responsible for severe fungal infection in CGD. The disease is also characterised by abnormally exuberant inflammatory responses leading to granuloma formation, such as granulomatous enterocolitis, genitourinary obstruction, and poor wound healing. We have shown that activation of proinflammatory caspase-1 and IL-1β secretion are elevated in CGD monocytes, especially in cells derived from symptomatic patients with inflammatory complications. A dual role for NADPH oxidase in control of infections and of inflammation is thus likely. Macroautophagy is a cytoprotective process that sequesters cytoplasmic material and delivers it to lysosomes for degradation and recycling. In addition, it has recently been implied in the innate immune response to extracellular pathogens after phagocytosis in an NADPH oxidase dependent way, in ER and Golgi apparatus independent exocytosis and in the control of the inflammasome. Defective inflammasome control has been described to lead to caspase-1 activation and IL-1β secretion in a set of rare autoinflammatory diseases. Mutations in genes involved in macroautophagy have been found associated with Morbus Crohn, an inflammatory bowel disease which clinically and pathologically strongly resembles CGD colitis. Taken together, defective macroautophagy may represent the missing link between the two main features of CGD: overwhelming infection and exuberant inflammation. The present proposal aims first at unravelling the role of macroautophagy in the CGD disease process with regard to NADPH oxidase function in two types of phagocytes – neutrophils which are first line of defence against infections, and macrophages which limit inflammatory reactions. The second objective of the proposal is identification of new therapeutic targets, and efficient correction of defective immune defence and hyperinflammation by novel gene therapy (GT) approaches. The previous results of our group on GT for CGD have shown that a GT approach for treatment of this devastating disease is feasible and may substantially contribute to improve patient’s health. Based on the results from this trial, future GT vectors have to balance sufficient transgene expression and functional efficiency with a minimum of transactivation activity. In the present proposal, self-inactivating (SIN)-retroviral vector designs conferring myelospecific expression and genome engineering strategies for transgene insertion into safe genomic harbours will be compared with regard to optimal control of infections and inflammation. CGD patient derived induced pluripotent stem cells will be used for that purpose. Altogether this model could serve as definitive proof of functional efficiency and safety of defined GT vectors before clinical use in future human gene therapy trials for CGD. |
||
| Keywords / Suchbegriffe | inflammasome, macroautophagy, CGD | ||
| Project leadership and contacts / Projektleitung und Kontakte |
|
||
| Funding source(s) / Unterstützt durch |
Others Gebert Rüf Stiftung, Programme “Rare Diseases – New approaches“ |
||
| In collaboration with / In Zusammenarbeit mit |
|
||
| Duration of Project / Projektdauer | Feb 2011 to May 2013 |