News release, March 23, 2011
Calprotectin against life-threatening moulds
An infection with the mould "Aspergillus" often kills patients with chronic granulomatous disease (CGD). Researchers from the University of Zurich and the University Children's Hospital Zurich shows now, that calprotectin is a key player for the immune defence against infection with "Aspergillus". The study may eventually lead to a new treatment modality of CGD patients.
Fungal infections with moulds can cause life-threatening health problems in patients with chronic neutropenia, or neutrophil dysfunction such as chronic granulomatous disease (CGD). CGD is a genetic severe immune deficiency disease that occurs at a frequency of one in 70,000 newborns per year worldwide. Children with CGD often suffer from life-threatening microbial infections with bacteria and moulds, due to a defect in phagocyte NADPH oxidase. Particularly, infections with Aspergillus spp. often kill CGD patients, before bone marrow transplantation or gene therapy can be performed. While healthy individuals’ white blood cells, also called neutrophils, release reactive oxygen species by action of the NADPH oxidase to kill and digest invading pathogens, the neutrophils in CGD patients lack the ability to kill these microbes.
Janine Reichenbach, consultant in Clinical Immunology and research group leader at the Division of Immunology/Haematology/BMT, University Children’s Hospital Zurich is studying mechanisms of innate immunity against infections. In earlier studies, in collaboration with Prof. A. Zychlinsky’s group at the Max Planck Institute for Infection Biology, Berlin, Germany, her group found that normal neutrophils form extracellular structures, called neutrophil extracellular traps or NETs, which catch and trap Aspergillus fungi for efficient control of infection. NETs are web-like structures made of chromatin and decorated with antimicrobial proteins.
In collaboration with researchers at the Umeå University in Sweden, the scientists from University Children's Hospital in Zurich found new details behind CGD. They compared the function of a CGD patient's neutrophils before and after gene therapy, performed at the University Children's Hospital in Zurich. “Our results clearly show that the antimicrobial calprotectin released within NETs is also important for the neutrophils immune defence against Aspergillus infection,” says Janine Reichenbach.
Together with PhD student Matteo Bianchi in her group at University Children’s Hospital Zurich and researchers in Umeå, Janine Reichenbach found that neutrophils from the CGD patient did not form NETs and were not able to release calprotectin before gene therapy. Therefore neutrophils were not able to kill and digest Aspergillus. “We found that after gene therapy corrected neutrophils could release calprotectin and the NET structure,” says Matteo Bianchi. “Our experiment showed that calprotectin is a key player for the neutrophils’ defence against Aspergillus infection.
“Our mechanistic study may eventually lead to a new treatment modality of CGD patients and prevent them from fungal infections until they have the possibility to receive gene therapy or bone marrow transplantation, which are more sustainable treatments,” says Janine Reichenbach.
Bianchi Matteo, Niemiec Maria J., Siler Ulrich, Urban Constantin F., Reichenbach Janine.: Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent. Journal of Allergy and Clinical Immunology. doi: 10.1016/j.jaci.2011.01.021