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Fighting Infection in CGD

Infections are a major threat to the health of people affected by CGD. The CGD Society supports work that helps to develop models that mimic human CGD disease processes. We also fund research that advances the development of better treatments for bacterial and fungal infections.

Since 1997 we have invested £887,208 in funding for 11 projects. The funding has resulted in:

  • the successful completion of two PhD studentships, assisting with building
  • knowledge and training future researchers
  • proof of principle data that have influenced a further $4.55m in research funding
  • the development of CGD cell lines, which can be used for a variety of research purposes
  • 14 peer-reviewed publications.

Here we summarise the grants we have funded and their outcomes.

Investigating new treatments for invasive aspergillosis in CGD

Grant awarded to: Professors Adilia Warris and Gordon D. Brown, Institute of Medical Sciences, University of Aberdeen

Amount: £14,141 over one year ending in 2018

Official title: ‘Assessing new treatment modalities to improve the outcome of invasive aspergillosis in CGD patients’

Aim: The condition invasive aspergillosis (IA) is a serious, life-threatening problem for people with CGD. IA can be caused by the fungi Aspergillus fumagatus and Aspergillus nidulans.

This study aimed to provide essential information on how best to prevent and treat IA in CGD patients. It tested a combination of antifungals and modulators of IL-1 to target both inflammation and fungal growth in a mouse model of aspergillosis in CGD.

Outcomes and benefits: The value of two anti-inflammatory treatments – hydroxychloroquine and Anakinra® – was assessed to determine their value in improving the outcomes of CGD mouse models infected either with Aspergillus fumagatus or Aspergillus nidulans.

Prophylactic hydroxychloroquine was shown to reduce mortality and infection rate in mice infected with Aspergillus nidulans but did not show any benefit for mice infected with Aspergillus fumagatus. The use of Anakinra®, either alone or in combination with the antifungal drug Voriconazole, did not improve the outcome of IA.

Work is ongoing to further explore the findings before recommendations can be made for treating IA in CGD patients.


Developing new cell models

Grant awarded to: Professors Lyle Armstrong, Majlinda Lako, William James and Reinhard Seger, Institute of Human Genetics and the North East England Stem Cell Institute, Newcastle University; Sir William Dunn School of Pathology, University of Oxford and University Children’s Hospital Zurich, Switzerland

Amount: £145,369 over two years ending in 2013. This work was supported with a generous donation of £30,347 from the Belron World Conference Foundation

Official title: ‘Using induced pluripotent stem cell technology to model human CGD disease’

Aim: There are currently few models with which to study human CGD. This project aimed to generate new CGD models by reprogramming skin cells from people with CGD, using key genetic triggers that turn back the cells’ biological clock so they become stem cells capable of generating many different cell types, including the white blood cells affected in CGD.

Outcomes and benefits: Different cell lines called induced pluripotent stem cells (iPSCs), carrying different CGD defects, were generated and characterised. These cell lines can be grown in unlimited numbers in the laboratory for use in research and in the future for treating patients. They have real advantages for studying the biology of CGD and represent an important tool for modelling CGD disease, screening candidate drugs and testing gene therapies.

Publications resulting from this work:

Derivation and functional analysis of patient-specific induced pluripotent stem cells as an in vitro model of chronic granulomatous disease
Jiang Y, Cowley SA, Siler U, Melguizo D, Tilgner K, Browne C, Dewilton A, Przyborski S, Saretzki G, James WS, Seger RA, Reichenbach J, Lako M, Armstrong L.
Stem Cells, 2012 April; 30(4): 599–611.
Published online 2012, February 6


Aspergillus NETs and CGD

Grant awarded to: Dr Janine Reichenbach and PhD candidate Matteo Bianchi,
University Children’s Hospital Zurich, Switzerland

Amount: £53,034 over two years ending in 2012

Official title: ‘Role of neutrophil extracellular traps (NETs) in Aspergillus infection and granulomatous inflammation in CGD’

Aim: The project aimed to study the role of neutrophil extracellular traps (NETs) in fighting Aspergillus infections and to understand the implications for CGD gene therapy. NETs are net-like structures produced by neutrophils. NETs trap and bind microbes and provide a high local concentration of chemicals to kill germs efficiently.

Outcomes and benefits: The work demonstrated that NETs play an important role in the fight against Aspergillus infections in healthy cells by inhibiting the growth of fungal spores or their hyphae (filaments that branch out of the fungal spore). CGD cells are not able to produce Aspergillus NETs and this inability to form NETs might explain the vulnerability of people with CGD to Aspergillus infections.

Gene therapy for CGD was able to restore NET formation transiently and resulted in the clearing of fungal infections in patients treated in this way. Further research showed that antifungal compounds have to be released and concentrated by the NETs for them to be effective, and the work discovered the chemical calprotectin to be the main antifungal agent within NETs. Although calprotectin was already known to have antibacterial and antifungal properties, discovery of its function within NETs to inhibit the growth of Aspergillus was a new step forward.

More information was gained on how the CGD defect affects how cells do their work properly to kill Aspergillus fungi. Future plans will study NET formation in cells from patients with X-linked CGD and autosomal recessive CGD, as well as asymptomatic X-CGD carriers, who have different percentages of oxidase positive cells. This will give important information on how much oxidase function needs to be restored by gene therapy to give protection against Aspergillus infections.

Publications resulting from this work:

Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent
Bianchi M, Niemiec MJ, Siler U, Urban CF, Reichenbach J.
Journal of Allergy and Clinical Immunology, 2011 May; 127(5): 1243–52.

Comment in
Journal of Allergy and Clinical Immunology, 2011 Sep; 128(3): 686–7; author reply 687–8.

Restoration of NET formation by gene therapy in CGD controls aspergillosis
Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, Reichenbach J. Blood, 2009 Sep 24; 114(13): 2619–22.

Actinomyces in chronic granulomatous disease: an emerging and unanticipated pathogen
Reichenbach J, Lopatin U, Mahlaoui N, Beovic B, Siler U, Zbinden R, Seger RA, Galmiche L, Brousse N, Kayal S, Güngör T, Blanche S, Holland SM.
Clinical Infectious Diseases, 2009 Dec 1; 49(11): 1703–10.

PhD thesis, University of Zurich: ‘Gene therapy for chronic granulomatous disease and anti-Aspergillus activity of reconstituted neutrophil extracellular trap formation’
Submitted by Matteo Bianchi.


Finding new ways to treat abscesses in CGD

Grant awarded to: Dr Brian Cobb and PhD candidate Miss Colleen Lewis, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Amount: £58,487 over two years ending in 2010

Official title: ‘Oxidative balance and immune responses in CGD: novel therapeutic paradigms’

Aim: Abscesses are the immune system’s way of quarantining harmful microbes within the body. They are a common feature of CGD. For people with CGD, abscesses are very painful and often require surgical drainage because they prevent antibiotics from working and can serve as reservoirs leading to larger, more serious systemic infections. This project aimed to understand more about how abscesses are formed and to develop better treatments.

Outcomes and benefits: The researchers found that the chemical nitric oxide (NO) was shown to play a major part in abscess formation. CGD mice produced 10-times more of the chemical mediator NO than healthy mice in response to a bacterial infection. In CGD mice, the high levels of NO were also sustained over a longer period of time.

This overproduction of NO coincided with increased inflammation and severe abscess formation. Neutrophils and macrophages were shown to be the source of NO and this activated other immune cells, contributing further to abscess formation. Significantly, the researchers were able to show that lowering NO production using a novel drug to levels seen in healthy mice, reduced the number and severity of abscesses in CGD mice.

This work paved the way for a potential new treatment option for resolving infections in CGD and preventing abscess and granuloma formation.

In 2008 Dr Cobb was awarded a National Institutes of Health (NIH) Director’s New Innovator Award and $2.35m over five years to continue this work that has the potential to benefit many other conditions.

Publications resulting from this work:

Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production
Lewis CJ and Cobb BA.
European Journal of Immunology, 2011 Sep; 41(9): 2562–2572.

Carbohydrate oxidation acidifies endosomes, regulating antigen processing and TLR9 signaling
Lewis CJ, Cobb BA.
Journal of Immunology, 2010 Apr 1; 184(7): 3789–800.


Understanding fungal infections and inflammation

Grant awarded to: Professor Luigina Romani and Dr Silvia Bozza, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy

Amount: £49,970 over one year ending in 2008

Official title: ‘Development of anti-inflammatory therapies in CGD’

Aim: To find ways of dampening down the inflammatory response that occurs following Aspergillus infections.

Outcomes and benefits: The work gave valuable new insights into the role of a particular type of T-lymphocyte cell population in CGD inflammation and tested ways of reducing inflammation. The researchers were able to show that the drug Pentraxin 3 could inhibit local fungal growth and the spread of infection to Aspergillus in animal models of CGD.

This study highlighted a possible new way of treating fungal infections in CGD.

Publications resulting from this work:

Exogenous Pentraxin 3 restores antifungal resistance and restrains inflammation in murine chronic granulomatous disease
D’Angelo C, De Luca A, Zelante T, Bonifazi P, Moretti S, Giovannini G, Iannitti RG, Zagarella S, Bozza S, Campo S, Salvatori G, Romani L.
Journal of Immunology, Oct 1; 183(7): 4609–18.


Development of a vaccine against fungal infections

Grant awarded to: Dr Brahm Segal and Dr John Subjeck, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

Amount: £97,000 over two years ending in 2008

Official title: ‘Development of an Aspergillus vaccine’

Aim: Infection caused by the fungi Aspergillus is a serious cause of illness and mortality in CGD and in many other diseases affecting the immune system. The project aimed to develop a vaccine against Aspergillus and intrinsic to this was the further understanding of how the enzyme affected in CGD (NADPH oxidase) regulates inflammation.

Outcomes and benefits: The strategic development of the vaccine was found to be crucially dependent on understanding more about how the defect in CGD influences interactions between different types of immune cells and how this causes inflammation. The project produced a vaccine candidate and identified potential therapeutic targets, such as Nrf2 activation, for dampening down excessive inflammation in CGD.

Overall, this project gave a greater insight into how to better design immune-based therapies, including vaccination.

The work funded by the CGD Society generated preliminary results that formed the basis for a five-year $2.2m award from the National Institutes of Health to Dr Segal to continue his work on the role of NADPH oxidase in regulating inflammation. This work will be centrally relevant to CGD, but it is also broadly important to other disorders of inflammation, such as autoimmune disorders and cancer.

"Without support from the CGD Society, we would not have been able to generate the preliminary results that led to this grant being funded." Dr Segal

Publications resulting from this work:

NADPH oxidase limits innate immune responses in the lungs in mice
Segal BH, Han W, Bushey JJ, Joo M, Bhatti Z, Feminella J, Dennis CG, Vethanayagam RR, Yull FE, Capitano M, Wallace PK, Minderman H, Christman JW, Sporn MB, Chan J, Vinh DC, Holland SM, Romani LR, Gaffen SL, Freeman ML, Blackwell TS.
PLoS One, 2010 Mar 16; 5(3): e9631.


Improving ways to kill Aspergillus fungi

Grant awarded to: Professor Judith Rhodes, Department of Pathology and Laboratory Medicine, Department of Internal Medicine, University of Iowa, USA

Amount: £34,695 over one year ending in 2008

Official title: ‘Non-oxidative, polymorphonuclear leukocyte-mediated anti-Aspergillus activity’

Aim: One key problem in CGD is the rapid spreading and growth of fungal infections. This project aimed to determine the mechanisms by which killing of Aspergillus fungus can be achieved, so fungal infections can be better controlled and treated in CGD.

Outcomes and benefits: The project helped better define the role of a particular cell pathway (called the PKA pathway) in the biology of Aspergillus fungi. This pathway is known to be central to the infectious and damaging properties of Aspergillus in CGD. The work found that when a certain part of the pathway was altered, the infectivity or virulence of Aspergillus was reduced in such a way that it inhibited the spread of the fungus.

This project has achieved a greater understanding and knowledge of an important regulatory pathway for Aspergillus growth and virulence in CGD. This will help in the development of better antifungal drugs for people with CGD.

Publications resulting from this work:

This work was presented as a poster at the 108th general meeting of the American Society for Microbiology.
‘Deletion of the Aspergillus fumigatus protein kinase A (PKA) regulatory subunit, pkaR, decreases virulence in a murine model of CGD’.
Fortwendel JR, Gibbons RS, Allen HL, Deepe GS, Newman S, Askew DS, Rhodes JC.


Development of a model to understand chronic aspergillosis in CGD

Grant awarded to: Professor Tom Rogers, Dr Elaine Bignell, Professor Arst Herb, Dr Ken Haynes and PhD candidate Suzy Turnbull, Department of Infectious Diseases, Imperial College London

Amount: £71,060 over three years ending in 2008

Official title: ‘Development of a model of chronic aspergillosis in p47phox CGD mice’

Aim: Aspergillosis is a common threat in CGD. Pulmonary aspergillosis, a fungal infection affecting the lungs, is a very serious infection, with pneumonia that can spread to other parts of the body. This PhD studentship aimed to find out more about how the healthy immune system clears Aspergillus lung infections and how and why the response of CGD patients differs and causes severe problems.

Outcomes and benefits: Animal models that more closely replicated the development of human aspergillosis were developed. This project identified some key differences in gene-marker expression in response to Aspergillus fungi between the healthy and the immuno-compromised state where disease develops. The work gave new insights into the mechanisms that govern fungal immunity in the lung and has been crucial for the establishment of fungal pathogenicity studies at Imperial College London.

Publications resulting from this work:

Impaired interferon-γ responses, increased interleukin-17 expression, and a tumor necrosis factor–α transcriptional program in invasive aspergillosis
Armstrong-James DP, Turnbull SA, Teo I, Stark J, Rogers NJ, Rogers TRF, Bignell E, Haynes K.
Journal of Infectious Diseases, 2009 Oct; 200(8): 1341–51.


Investigating how interferon gamma works

Grant awarded to: Professors Jerrold Weiss and William Nauseef, Department of Internal Medicine, University of Iowa, USA

Amount: £30,083 over one year ending in 2007

Official title: ‘Phagocytic oxidase: extracellular antimicrobial synergy. Effect of interferon gamma’

Aim: Gamma interferon (IFN) can sometimes be given to people with CGD to help reduce the frequency of serious bacterial infections. However, how this treatment works is not completely understood. This project aimed to explore one possible mechanism.

Outcomes and benefits: The project tested if the beneficial effect of IFN gamma observed in some CGD patients was due to increased activity of a certain enzyme called phospholipase A2, produced by cells of the immune system. This enzyme is known to be toxic to bacteria.

The results showed that the action of IFN gamma is not through increased phospholipase A2 enzyme activity but through the stimulation of other potent antimicrobial molecules. Unfortunately, the identification of these molecules was beyond the scope of the project.

Additionally the work highlighted species-dependent differences in the expression of the enzyme phospholipase A2. Although the results were negative, one avenue of research was explored. Useful information was gained on the best animal models to study the effects of IFN gamma.


Developing novel treatments for the most serious CGD infection: Aspergillus

Grant awarded to: Professor Tom Rogers, Dr Ken Haynes and Professor Arst Herb, Department of Infectious Diseases, Imperial College London

Amount: £152,410 over three years ending in 2004

Official title: ‘Investigation of the fungal pH regulatory system in the virulence of Aspergillus in CGD’

Aim: This project studied the way in which the Aspergillus family of fungi can adapt to changes in their growth environment. It also investigated if this adaptive mechanism could be an important factor in the ability of Aspergillus fungi to cause disease in CGD.

Outcomes and benefits: The group identified part of a pH-dependent protein, which allows growth adaptation to acid and alkaline conditions, as a potential antifungal drug target. Importantly, the group found that by manipulating specific components of the pH-dependent genes, they could increase and decrease the extent of the aspergillosis infection induced by the fungi in animal models of CGD. Most importantly, the study showed that infection in CGD mice could be fatal in the absence of fungal growth, indicating that inflammation caused by fungi is a major consideration.

This work was significant because the majority of the research into the diagnosis, pathology and treatment of Aspergillus infection predominantly uses animal models that have abnormally low number of neutrophils (known as neutropenia). The findings demonstrate that the extrapolation of data obtained in this way to the human condition of CGD may be of limited value in terms of improving prospects for people with CGD. It also indicates that studies using CGD models are vital to explore the infection processes in CGD.

Publications resulting from this work:

Virulence comparisons of Aspergillus nidulans mutants are confounded by the inflammatory response of p47phox-/- mice
Bignell E, Negrete-Urtasun S, Calcagno AM, Arst HN Jr, Rogers T, Haynes K.
Infection and Immunity, 2005 Aug; 73(8): 5204–7.

The Aspergillus pH-responsive transcription factor PacC regulates virulence
Bignell E, Negrete-Urtasun S, Calcagno AM, Haynes K, Arst HN Jr, Rogers T.
Molecular Microbiology, 2005 Feb; 55(4): 1072–84.


Development of animal models to study CGD

Grant awarded to: Professor Anthony Segal, Centre for Molecular Medicine, University College London

Amount: £125,000 over two years ending in 2000

Official title: ‘Assessment of bacterial killing and digestion by knockout mice lacking the NADPH oxidase and other neutrophil proteins’

Aim: To help reassess the role of the enzyme NADPH oxidase and reactive oxygen species in killing bacteria.

Outcomes and benefits: This research provided proof that the killing of bacteria is the function of the enzyme pathway that is faulty in CGD.

Publications resulting from this work:

How neutrophils kill microbes
Segal AW.
Annual Review of Immunology, 2005; 23: 197–223.

Reassessment of the microbicidal activity of reactive oxygen species and hypochlorous acid with reference to the phagocytic vacuole of the neutrophil granulocyte
Reeves EP, Nagl M, Godovac-Zimmermann J, Segal AW.
Journal of Medical Microbiology, 2003 Aug; 52 (Pt 8): 643–51.

Catalase negative Staphylococcus aureus retain virulence in mouse model of chronic granulomatous disease
Messina CG, Reeves EP, Roes J, Segal AW.
FEBS Letters, 2002 May 8; 518(1–3): 107–10.


How do cells kill bacteria? Implications for CGD

Grant awarded to: Professor Anthony Segal, Centre for Molecular Medicine, University College London

Amount: £55,959 over one year ending in 1998

Official title: ‘Killing and digestion of fungi by knockout CGD mice lacking the NAPDH oxidase as a model for the management of fungal infections in human patients’

Aim: To develop a model of the p47phox type of CGD in order to better understand disease processes.

Outcomes and benefits: This CGD Society-funded award established the p47phox-deficient CGD mouse model that has been invaluable in many CGD research studies in Professor Segal’s laboratory and other laboratories around the world.


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