Reichenbach
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Immunologie, Abteilung » Prof. Dr. Reinhard Seger » Reichenbach
Completed research project
| Title / Titel | Role of Neutrophil Extracellular Traps (NETs) in Aspergillus infection and granulomatous inflammation in CGD | ||||||
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| Abstract (PDF, 14 KB) | |||||||
| Summary / Zusammenfassung | Chronic granulomatous disease (CGD) patients have impaired NADPH oxidase function, resulting in poor antimicrobial activity of neutrophils including the inability to generate Neutrophil Extracellular Traps (NETs). Invasive aspergillosis is the leading cause of death in patients with CGD. It is still unclear how neutrophils control Aspergillus infection in healthy individuals. We hypothesise that neutrophils kill Aspergillus by NET formation and that a certain threshold of NADPH oxidase function is needed for efficient NET-killing. We plan to test this in vitro by NET Aspergillus killing assays of neutrophils from patients with X-linked CGD, autosomal-recessive CGD, as well as asymptomatic X-CGD carriers with variable percentages of oxidase positive cells. In addition to susceptibility to infection, patients with CGD are prone to develop severe inflammatory granulomatous lesions. We hypothesise that this again is linked to deficient NET formation, leading to deregulated inflammatory response through accumulation of neutrophils that cannot undergo NET-induced cell death. Since inflammatory granulomatous lesions are difficult to monitor in humans, we will test this by an in vivo granuloma model in CGD mice, involving subcutaneous injection of sterilized Aspergillus conidia. NET formation, clinical and histological granuloma resolution will be monitored before and after gene therapy, resulting in variable percentages of gene transduced cells. The aim of these assays is the development of an appropriate tool to monitor clinical efficiency of gene therapy in patients with CGD and to correlate NET formation to NADPH oxidase gene expression and reconstitution of NADPH oxidase function. |
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| Publications / Publikationen | Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, Reichenbach J. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood (2009) 114: 2619-22.Bianchi M, Niemiec MJ, Siler U, Urban CF and Reichenbach J. Restoration of anti-Aspergillus defense by NETs in human CGD after Gene Therapy is Calprotectin-dependent J Allergy Clin Immunol. Accepted for publication Jan 10th 2011 |
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| Keywords / Suchbegriffe | neutrophils, respiratory burst, NET formation | ||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Other links to external web pages | http://www.cgd.org.uk/ | ||||||
| Funding source(s) / Unterstützt durch |
Others Chronic Granulomatous Disorder Reseach Trust, UK |
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| In collaboration with / In Zusammenarbeit mit |
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| Duration of Project / Projektdauer | Apr 2009 to Jul 2011 |