Faculty Opinions recommendation of Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung.

2018 ◽  
Author(s):  
Ashraf Ibrahim
Keyword(s):  
Chronic Granulomatous Disease ◽  
Type I Interferon ◽  
Type I ◽  
Granulomatous Disease ◽  
Early Recruitment ◽  
Stimulation Of

scholarly journals Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
pp. e00422-18 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Michael J. Davis ◽  
Janyce A. Sugui ◽  
Tzvia Pinkhasov ◽  
Shannon Moyer ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Chronic Granulomatous Disease ◽  
Type I Interferon ◽  
Histopathological Examination ◽  
Survival Rates ◽  
Antifungal Drugs ◽  
Type I ◽  
Granulomatous Disease ◽  
Type I Ifn ◽  
Baseline Levels

ABSTRACTInvasive aspergillosis (IA) remains the primary cause of morbidity and mortality in chronic granulomatous disease (CGD) patients, often due to infection byAspergillusspecies refractory to antifungals. This motivates the search for alternative treatments, including immunotherapy. We investigated the effect of exogenous type I interferon (IFN) activation on the outcome of IA caused by threeAspergillusspecies,A. fumigatus,A. nidulans, andA. tanneri, in CGD mice. The animals were treated with poly(I):poly(C) carboxymethyl cellulose poly-l-lysine (PICLC), a mimetic of double-stranded RNA, 24 h preinfection and postinfection. The survival rates and lung fungal burdens were markedly improved by PICLC immunotherapy in animals infected with any one of the threeAspergillusspecies. While protection from IA was remarkable, PICLC induction of type I IFN in the lungs surged 24 h posttreatment and returned to baseline levels by 48 h, suggesting that PICLC altered early events in protection against IA. Immunophenotyping of recruited leukocytes and histopathological examination of tissue sections showed that PICLC induced similar cellular infiltrates as those in untreated-infected mice, in both cases dominated by monocytic cells and neutrophils. However, the PICLC immunotherapy resulted in a marked earlier recruitment of the leukocytes. Unlike with conidia, infection withA. nidulansgermlings reduced the protective effect of PICLC immunotherapy. Additionally, antibody depletion of neutrophils totally reversed the protection, suggesting that neutrophils are crucial for PICLC-mediated protection. Together, these data show that prophylactic PICLC immunotherapy prerecruits these cells, enabling them to attack the conidia and thus resulting in a profound protection from IA.IMPORTANCEPatients with chronic granulomatous disease (CGD) are highly susceptible to invasive aspergillosis (IA). WhileAspergillus fumigatusis the most-studiedAspergillusspecies, CGD patients often suffer IA caused byA. nidulans,A. tanneri, and other rare species. These non-fumigatus Aspergillusspecies are more resistant to antifungal drugs and cause higher fatality rates thanA. fumigatus. Therefore, alternative therapies are needed to protect CGD patients. We report an effective immunotherapy of mice infected with threeAspergillusspecies via PICLC dosing. While protection from IA was long lasting, PICLC induction of type I IFN surged but quickly returned to baseline levels, suggesting that PICLC was altering early events in IA. Interestingly, we found responding immune cells to be similar between PICLC-treated and untreated-infected mice. However, PICLC immunotherapy resulted in an earlier recruitment of the leukocytes and suppressed fungal growth. This study highlights the value of type I IFN induction in CGD patients.

scholarly journals Detection of carriers of the autosomal form of chronic granulomatous disease

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 505-507 ◽  
Author(s):  
AJ Verhoeven ◽  
ML van Schaik ◽  
D Roos ◽  
RS Weening
Keyword(s):  
Chronic Granulomatous Disease ◽  
Respiratory Burst ◽  
Granulomatous Disease ◽  
Mosaic Pattern ◽  
Simple Method ◽  
Nbt Test ◽  
Activated Neutrophils ◽  
Slide Test ◽  
Microscopic Slide ◽  
Stimulation Of

The NADPH:O2 oxidoreductase catalyzing the respiratory burst in activated phagocytes from healthy individuals is not operative in phagocytes from patients with chronic granulomatous disease (CGD). In a microscopic slide test using the dye nitroblue tetrazolium (NBT), carriers of X-linked CGD can be recognized by a mosaic pattern of NBT- positive and NBT-negative cells, governed by the expression of an unaffected or an affected X chromosome, respectively. Until now, it has not been possible to detect carriers of the autosomal form of CGD (other than by family studies) because all cells of these carriers stain positive in the NBT test. We have investigated whether neutrophils from carriers of autosomal CGD can be recognized by measurement of the rate of oxygen uptake upon stimulation of the cells. It was found that with the phorbol ester PMA as a stimulus, the respiratory burst is significantly lower in autosomal CGD carriers. With serum-treated zymosan as a stimulus, no difference between controls and carriers was observed. The addition of f-Met-Leu-Phe (1 microM) to PMA-activated neutrophils of control donors caused a transient increase in oxygen consumption of about 40%. Under these conditions, an increase of more than 100% was observed in neutrophils from carriers of autosomal CGD. These findings provide a simple method for the detection of carriers of the autosomal form of CGD.

scholarly journals Protein phosphorylation in neutrophils from patients with p67-phox- deficient chronic granulomatous disease

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4404-4410 ◽  
Author(s):  
PG Heyworth ◽  
J Ding ◽  
RW Erickson ◽  
DJ Lu ◽  
JT Curnutte ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Protein Phosphorylation ◽  
Inorganic Phosphate ◽  
Granulomatous Disease ◽  
Cell Stimulation ◽  
Phagocyte Oxidase ◽  
Stimulation Of

Neutrophils are known to contain a major 67-kD protein that undergoes enhanced phosphorylation and translocation to the membrane during cell stimulation. Recent studies have assumed that this 67-kD phosphoprotein is the 67-kD subunit of the phagocyte oxidase (p67-phox). We compare here the protein phosphorylation patterns in lysates of normal neutrophils and neutrophils from patients with chronic granulomatous disease (CGD) that are completely deficient in p67-phox. The phosphoproteins were labeled by incubation of the cells with radioactive inorganic phosphate (32Pi) or by the addition of [gamma- 32P]ATP to electropermeabilized neutrophils. With either method, stimulation of the normal or CGD cells always resulted in an enhanced incorporation of 32p into two proteins in the 67-kD area. The extent of phosphorylation of these two proteins was very similar in the normal and CGD cells when permeabilized neutrophils loaded with [gamma - 32P]ATP were compared. Moreover, no overall differences in the protein phosphorylation patterns were observed between the normal and CGD cells. Our data indicate that the major 67-kD phosphoproteins observed in stimulated neutrophils are clearly different from p67-phox.

scholarly journals NADPH-binding component of the respiratory burst oxidase system: studies using neutrophil membranes from patients with chronic granulomatous disease lacking the beta-subunit of cytochrome b558.

1994 ◽  
Vol 179 (1) ◽  
pp. 291-297 ◽  
Author(s):  
S Tsunawaki ◽  
H Mizunari ◽  
H Namiki ◽  
T Kuratsuji
Keyword(s):  
Chronic Granulomatous Disease ◽  
Respiratory Burst ◽  
Beta Subunit ◽  
Human Neutrophils ◽  
Granulomatous Disease ◽  
Oxidase System ◽  
Cytochrome B558 ◽  
Respiratory Burst Oxidase ◽  
Stimulation Of ◽  
Binding Component

The NADPH-binding site of the respiratory burst oxidase system of neutrophils has been proposed to be either at a cytosolic component or at the beta-subunit of cytochrome b558. In this study, affinity labeling of resting and stimulated membranes, the latter having been assembled by all of the oxidase components from both membrane and cytosol, was carried out using [32P]NADPH dialdehyde (oNADPH). Stimulation of human neutrophils with PMA greatly increased O2(-)-generating activity and caused considerable translocation of the cytosolic components p47phox and p67phox. Nevertheless, PMA stimulation did not produce a labeled band which included positions at 47, 67, and approximately 32 kD. The most intense band reflected a molecular mass of 84 kD regardless of the state of activation, but a labeled band was never found near the beta-subunit (91 kD) of cytochrome b558. This 84-kD protein was further confirmed in neutrophils of 14 patients with gp91phox-deficient X-linked chronic granulomatous disease. These results indicate that the NADPH-binding component is not recruited from the cytosol, and also, that a membranous redox component besides cytochrome b558 must be involved in the NADPH oxidase system.

scholarly journals Protein kinases potentially capable of catalyzing the phosphorylation of p47-phox in normal neutrophils and neutrophils of patients with chronic granulomatous disease

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 940-947
Author(s):  
J Ding ◽  
JA Badwey ◽  
RW Erickson ◽  
KJ Balazovich ◽  
JT Curnutte
Keyword(s):  
Chronic Granulomatous Disease ◽  
Protein Kinases ◽  
Granulomatous Disease ◽  
Amino Acid Residues ◽  
Peptide Substrate ◽  
Uncharacterized Protein ◽  
Kinase C ◽  
Multiple Protein ◽  
Novel Protein ◽  
Stimulation Of

A procedure for uncovering novel protein kinases was used to search for enzymes in neutrophils that may catalyze the phosphorylation of the 47- Kd subunit of the NADPH oxidase system (p47-phox). This component of the oxidase can undergo phosphorylation on multiple sites. The method is based on the ability of renatured kinases to recognize exogenous substrates fixed in gels. We report that neutrophils contain several uncharacterized protein kinases that catalyze the phosphorylation of a peptide substrate that corresponds to amino acid residues 297 through 331 of p47-phox. Some of these enzymes are strongly activated on stimulation of the cells with phorbol 12-myristate 13-acetate (PMA). The results indicate that the phosphorylation of p47-phox in neutrophils may be more complicated than previously appreciated and may involve multiple protein kinases. In addition, we have examined both the renaturable protein kinases and the properties of protein kinase C (PKC) in neutrophils from patients with chronic granulomatous disease (CGD) who are deficient in cytochrome b558. Previous studies have shown that these cells exhibit incomplete phosphorylation of p47-phox on stimulation. In this study, we were unable to detect any alterations in the renaturable protein kinases or PKC in CGD neutrophils that could explain these defects in the phosphorylation of p47-phox.

scholarly journals Chronic granulomatous disease 2018: advances in pathophysiology and clinical management

2019 ◽  
Vol 6 (1) ◽  
pp. 1-16
Author(s):  
Reinhard A. Seger
Keyword(s):  
Chronic Granulomatous Disease ◽  
Clinical Management ◽  
Lentiviral Vector ◽  
Host Cells ◽  
Type I ◽  
Safe Procedure ◽  
Granulomatous Disease ◽  
Phagocytic Cells ◽  
Hematopoietic Stem ◽  
Anti Inflammatory

Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder of phagocytic cells resulting in failure to kill a characteristic spectrum of bacteria and fungi and to resolve inflammation. The last few years have witnessed major advances in pathogenesis and clinical management of the disease: Better understanding of 3 physiologic anti-inflammatory functions of NADPH oxidase-derived reactive oxygen species: Promotion of the clearance of dying host cells, suppression of inflammasomes, and regulation of type I interferon signalling. This insight is opening new avenues for targeted drug interventions. Advances in reduced intensity conditioning (RIC) for allogeneic hematopoietic stem cell transplantation (HSCT) make it a promising and safe procedure even for fragile patients with ongoing severe infection or hyperinflammation. Encouraging early data of a multicenter trial of gene-replacement therapy using a self-inactivated lentiviral vector. Combining targeted anti-infectious/anti-inflammatory measures and considering extended indications for curative HSCT are key to improving patient outcome further. Gene therapy will likely become a viable option for disease correction, but long-term assessment is not yet possible. Statement of novelty: We discuss important advances in pathogenesis and treatment of CGD that will change our approach to clinical management.

scholarly journals Protein kinases potentially capable of catalyzing the phosphorylation of p47-phox in normal neutrophils and neutrophils of patients with chronic granulomatous disease

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 940-947 ◽  
Author(s):  
J Ding ◽  
JA Badwey ◽  
RW Erickson ◽  
KJ Balazovich ◽  
JT Curnutte
Keyword(s):  
Chronic Granulomatous Disease ◽  
Protein Kinases ◽  
Granulomatous Disease ◽  
Amino Acid Residues ◽  
Peptide Substrate ◽  
Uncharacterized Protein ◽  
Kinase C ◽  
Multiple Protein ◽  
Novel Protein ◽  
Stimulation Of

Abstract A procedure for uncovering novel protein kinases was used to search for enzymes in neutrophils that may catalyze the phosphorylation of the 47- Kd subunit of the NADPH oxidase system (p47-phox). This component of the oxidase can undergo phosphorylation on multiple sites. The method is based on the ability of renatured kinases to recognize exogenous substrates fixed in gels. We report that neutrophils contain several uncharacterized protein kinases that catalyze the phosphorylation of a peptide substrate that corresponds to amino acid residues 297 through 331 of p47-phox. Some of these enzymes are strongly activated on stimulation of the cells with phorbol 12-myristate 13-acetate (PMA). The results indicate that the phosphorylation of p47-phox in neutrophils may be more complicated than previously appreciated and may involve multiple protein kinases. In addition, we have examined both the renaturable protein kinases and the properties of protein kinase C (PKC) in neutrophils from patients with chronic granulomatous disease (CGD) who are deficient in cytochrome b558. Previous studies have shown that these cells exhibit incomplete phosphorylation of p47-phox on stimulation. In this study, we were unable to detect any alterations in the renaturable protein kinases or PKC in CGD neutrophils that could explain these defects in the phosphorylation of p47-phox.

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