scholarly journals Xanthine Oxidase Contributes to Host Defense against Burkholderia cepacia in the p47phox−/− Mouse Model of Chronic Granulomatous Disease

2000 ◽  
Vol 68 (4) ◽  
pp. 2374-2378 ◽  
Author(s):  
Brahm H. Segal ◽  
Nobuaki Sakamoto ◽  
Mayur Patel ◽  
Kosei Maemura ◽  
Andrew S. Klein ◽  
...  
Keyword(s):  
Mouse Model ◽  
Chronic Granulomatous Disease ◽  
Xanthine Oxidase ◽  
Host Defense ◽  
Burkholderia Cepacia ◽  
Fungal Infections ◽  
Granulomatous Disease ◽  
Life Threatening ◽  
Reactive Oxidant ◽  
Reactive Oxidants

ABSTRACT Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide and downstream microbicidal reactive oxidants, leading to recurrent life-threatening bacterial and fungal infections. Xanthine oxidase (XO) is another enzyme known to produce superoxide in many tissues. Using the p47 phox−/− mouse model of CGD, we evaluated the residual antibacterial activity of XO. Clearance of Burkholderia cepacia, a major pathogen in CGD, was reduced in p47 phox−/− mice compared to that in wild-type mice and was further inhibited in p47 phox−/− mice by pretreatment with the specific XO inhibitor allopurinol. Hepatic B. cepaciaburden was similar in the two genotypes, but allopurinol significantly reduced net hepatic killing and killing efficiency only in p47 phox−/− mice. Clearance and killing of intravenous Escherichia coli was intact in p47 phox−/− mice and was unaffected by pretreatment with allopurinol. In CGD, XO may contribute to host defense against a subset of reactive oxidant-sensitive pathogens.

scholarly journals The p47phox mouse knock-out model of chronic granulomatous disease.

1995 ◽  
Vol 182 (3) ◽  
pp. 751-758 ◽  
Author(s):  
S H Jackson ◽  
J I Gallin ◽  
S M Holland
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Critical Role ◽  
Granulomatous Inflammation ◽  
Mammalian Host ◽  
Granulomatous Disease ◽  
Knock Out ◽  
Phagocyte Nadph Oxidase ◽  
Life Threatening

Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice produced no superoxide and killed staphylococci ineffectively. p47phox-/- mice developed lethal infections and granulomatous inflammation similar to those encountered in human CGD patients. This model mirrors human CGD and confirms a critical role for the phagocyte NADPH oxidase in mammalian host defense.

Topics in Chronic Granulomatous Disease

PEDIATRICS ◽  
1991 ◽  
Vol 88 (1) ◽  
pp. 183-185
Author(s):  
SHIGENOBU UMEKI
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Host Defense ◽  
Superoxide Anion ◽  
Fungal Infections ◽  
Regulatory Elements ◽  
Granulomatous Disease ◽  
Phagocytic Cells ◽  
Oxidase System ◽  
Membrane Bound

To the Editor.— Such phagocytic cells as neutrophils and macrophages are crucial elements in the host defense against bacterial [See table in the PDF file] and fungal infections. Microbicidal activity depends to a large extent on NADPH oxidase system, which can be activated by stimuli (bacteria, fungi) and which generates the superoxide anion and other highly reactive forms of reduced oxygen.1,2 The neutrophil NADPH oxidase system is composed functionally of membrane-bound catalytic components (which consist of at least two constituents, the low potential cytochrome b5583-5 and flavoprotein5) and soluble cytosolic components6,7 which participate as either catalytic or regulatory elements.

scholarly journals An Uncommon Feature of Chronic Granulomatous Disease in a Neonate

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Razieh Afrough ◽  
Sayyed Shahabeddin Mohseni ◽  
Setareh Sagheb
Keyword(s):  
Mortality Rate ◽  
Chronic Granulomatous Disease ◽  
High Mortality ◽  
Neonatal Period ◽  
Fungal Infections ◽  
Granuloma Formation ◽  
Granulomatous Disease ◽  
Life Threatening

Chronic Granulomatous Disease (CGD) represents recurrent life-threatening bacterial and fungal infections and granuloma formation with a high mortality rate. CGD’s sign and symptoms usually appear in infancy and children before the age of five; therefore, its presentation in neonatal period with some uncommon features may be easily overlooked. Here we describe a case of CGD in a 24-day-old boy, presenting with a diffuse purulent vesiculopustular rash and multiple osteomyelitis.

scholarly journals Effect of Amphotericin B and Micafungin Combination on Survival, Histopathology, and Fungal Burden in Experimental Aspergillosis in the p47phox−/− Mouse Model of Chronic Granulomatous Disease

2006 ◽  
Vol 50 (2) ◽  
pp. 422-427 ◽  
Author(s):  
Carly G. Dennis ◽  
William R. Greco ◽  
Yseult Brun ◽  
Richard Youn ◽  
Harry K. Slocum ◽  
...  
Keyword(s):  
Mouse Model ◽  
Chronic Granulomatous Disease ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Rank Order ◽  
Granulomatous Disease ◽  
Knockout Mouse Model ◽  
Fungal Burden ◽  
Group I ◽  
Significant Difference

ABSTRACT Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase characterized by recurrent life-threatening bacterial and fungal infections. We characterized the effects of single and combination antifungal therapy on survival, histopathology, and laboratory markers of fungal burden in experimental aspergillosis in the p47 phox − / − knockout mouse model of CGD. CGD mice were highly susceptible to intratracheal Aspergillus fumigatus challenge, whereas wild-type mice were resistant. CGD mice were challenged intratracheally with a lethal inoculum (1.25 × 104 CFU/mouse) of A. fumigatus and received one of the following regimens daily from day 0 to 4 after challenge (n = 19 to 20 per treatment group): (i) vehicle, (ii) amphotericin B (intraperitoneal; 1 mg/kg of body weight), (iii) micafungin (intravenous; 10 mg/kg), or (iv) amphotericin B plus micafungin. The rank order of therapeutic efficacy based on prolonged survival, from highest to lowest, was as follows: amphotericin B plus micafungin, amphotericin B alone, micafungin alone, and the vehicle. Lung histology showed pyogranulomatous lesions and invasive hyphae, but without hyphal angioinvasion or coagulative necrosis. Treatment with micafungin alone or combined with amphotericin B produced swelling of invasive hyphae that was not present in mice treated with the vehicle or amphotericin B alone. Assessment of lung fungal burden by quantitative PCR showed no significant difference between treatment groups. Serum galactomannan levels were at background despite documentation of invasive aspergillosis by histology. Our findings showed the superior efficacy of the amphotericin B and micafungin combination compared to either agent alone after A. fumigatus challenge and also demonstrated unique features of CGD mice as a model for experimental aspergillosis.

scholarly journals Case Report: Secondary Hemophagocytic Lymphohistiocytosis With Disseminated Infection in Chronic Granulomatous Disease—A Serious Cause of Mortality

2020 ◽  
Vol 11 ◽  
Author(s):  
Jacqueline D. Squire ◽  
Stephanie N. Vazquez ◽  
Angela Chan ◽  
Michele E. Smith ◽  
Deepak Chellapandian ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
Chronic Granulomatous Disease ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Fungal Infections ◽  
Primary Immune Deficiency ◽  
Granulomatous Disease ◽  
Simultaneous Treatment ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Life Threatening

Chronic granulomatous disease (CGD) is a primary immune deficiency due to defects in phagocyte respiratory burst leading to severe and life-threatening infections. Patients with CGD also suffer from disorders of inflammation and immune dysregulation including colitis and granulomatous lung disease, among others. Additionally, patients with CGD may be at increased risk of systemic inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The presentation of HLH often overlaps with symptoms of systemic inflammatory response syndrome (SIRS) or sepsis and therefore can be difficult to identify, especially in patients with a primary immune deficiency in which incidence of infection is increased. Thorough evaluation and empiric treatment for bacterial and fungal infections is necessary as HLH in CGD is almost always secondary to infection. Simultaneous treatment of infection with anti-microbials and inflammation with immunosuppression may be needed to blunt the hyperinflammatory response in secondary HLH. Herein, we present a series of X-linked CGD patients who developed HLH secondary to or with concurrent disseminated CGD-related infection. In two patients, CGD was a known diagnosis prior to development of HLH and in the other two CGD was diagnosed as part of the evaluation for HLH. Concurrent infection and HLH were fatal in three; one case was successfully treated, ultimately receiving hematopoietic stem cell transplantation. The current literature on presentation, diagnosis, and treatment of HLH in CGD is reviewed.

Reconstitution of bactericidal activity in chronic granulomatous disease cells by glucose-oxidase–containing liposomes

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 3097-3105 ◽  
Author(s):  
Claudia E. Gerber ◽  
Gernot Bruchelt ◽  
Ulrike B. Falk ◽  
Andrea Kimpfler ◽  
Oliver Hauschild ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Glucose Oxidase ◽  
Whole Blood ◽  
Fungal Infections ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Confocal Laser ◽  
Granulomatous Disease ◽  
Life Threatening

Abstract Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by phagocytes devoid of a functioning nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The failure of CGD phagocytes to produce reactive oxygen species (ROS) results in a marked increase in the susceptibility of affected patients to life-threatening bacterial and fungal infections. This study investigated whether loading of CGD phagocytes with glucose oxidase (GO)–containing liposomes (GOLs) could restore cellular production of bactericidal ROS (eg, H2O2 and HOCl) in vitro. Results indicate that GO encapsulated in liposomes enabled NADPH oxidase-deficient phagocytes to use H2O2 for the production of highly bactericidal HOCl. The intracellular colocalization of bacteria and liposomes (or liposome-derived ferritin) was demonstrated by confocal laser microscopy and electron microscopy. After uptake of GOLs (approximately 0.2 U/mL at 1 mM total lipid concentration, size approximately 180 nm), CGD granulocytes produced HOCl levels comparable to those of normal phagocytes. Remarkably, after treatment with GOLs, CGD phagocytes killed Staphylococcus aureus as efficiently as normal granulocytes. Moreover, treated cells retained sufficient motility toward chemotactic stimuli as measured by chemotaxis assay. Side effects were evaluated by measuring the H2O2 concentrations and the production of methemoglobin in whole blood. These studies revealed that H2O2 produced by GOLs was degraded immediately by the antioxidative capacity of whole blood. Elevated methemoglobin levels were observed only after application of extremely high amounts of GOLs (2 U/mL). In summary, the application of negatively charged GOLs might provide a novel effective approach in the treatment of patients with CGD at high risk for life-threatening infections.

scholarly journals Virulence and Cellular Interactions of Burkholderia multivorans in Chronic Granulomatous Disease

2009 ◽  
Vol 77 (10) ◽  
pp. 4337-4344 ◽  
Author(s):  
Adrian M. Zelazny ◽  
Li Ding ◽  
Houda Z. Elloumi ◽  
Lauren R. Brinster ◽  
Fran Benedetti ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Burkholderia Cepacia ◽  
Cell Entry ◽  
Cellular Interactions ◽  
Granulomatous Disease ◽  
Burkholderia Multivorans ◽  
Healthy Donors ◽  
Cell Association ◽  
Life Threatening ◽  
Shed Light

ABSTRACT Chronic granulomatous disease (CGD) patients are susceptible to life-threatening infections by the Burkholderia cepacia complex. We used leukocytes from CGD and healthy donors and compared cell association, invasion, and cytokine induction by Burkholderia multivorans strains. A CGD isolate, CGD1, showed higher cell association than that of an environmental isolate, Env1, which correlated with cell entry. All B. multivorans strains associated significantly more with cells from CGD patients than with those from healthy donors. Similar findings were observed with another CGD pathogen, Serratia marcescens, but not with Escherichia coli. In a mouse model of CGD, strain CGD1 was virulent while Env1 was avirulent. B. multivorans organisms were found in the spleens of CGD1-infected mice at levels that were 1,000 times higher than those found in Env1-infected mice, which was coincident with higher levels of the proinflammatory cytokine interleukin-1β. Taken together, these results may shed light on the unique susceptibility of CGD patients to specific pathogens.

scholarly journals Adult-diagnosed Chronic Granulomatous Disease: The Need to Increase Awareness

2021 ◽  
Author(s):  
Joseph Baxter ◽  
Derek Smith ◽  
Charles Webb
Keyword(s):  
Chronic Granulomatous Disease ◽  
Lupus Erythematosus ◽  
Fungal Infections ◽  
Genetic Disorder ◽  
Immunosuppressive Drugs ◽  
Granulomatous Disease ◽  
Multiple Systems ◽  
Life Saving ◽  
Life Threatening ◽  
History Of

ABSTRACT Chronic granulomatous disease is genetic disorder characterized by the inability of phagocytes to produce sufficient oxidative burst needed to kill intracellular organisms. Patients have recurrent, life-threatening infections involving multiple systems including the lungs, skin, lymph nodes, and liver. The majority of patients with chronic granulomatous disease are diagnosed in childhood although some may present in adulthood due to a milder phenotype. Unfortunately, these patients may also present with concomitant autoimmune diseases. We describe a 48-year-old woman with a history of immune thrombocytopenia and systemic lupus erythematosus on immunosuppressive therapy. She developed subsequent bacterial and fungal infections initially attributed to immunosuppressive drugs. Further evaluation revealed the diagnosis of chronic granulomatous disease. We review the diagnosis and treatment of chronic granulomatous disease in hopes to increase awareness of this disease in adulthood in order to initiate potential life-saving prophylactic antibiotics.

scholarly journals Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art

2021 ◽  
Vol 7 (6) ◽  
pp. 451
Author(s):  
Georgios Karavalakis ◽  
Evangelia Yannaki ◽  
Anastasia Papadopoulou
Keyword(s):  
Host Defense ◽  
Hematopoietic Cell Transplantation ◽  
State Of The Art ◽  
Fungal Infections ◽  
Solid Organ Transplantation ◽  
Immunocompromised Host ◽  
Antifungal Drugs ◽  
Solid Organ ◽  
Cell Immunotherapy ◽  
Life Threatening

Despite the availability of a variety of antifungal drugs, opportunistic fungal infections still remain life-threatening for immunocompromised patients, such as those undergoing allogeneic hematopoietic cell transplantation or solid organ transplantation. Suboptimal efficacy, toxicity, development of resistant variants and recurrent episodes are limitations associated with current antifungal drug therapy. Adjunctive immunotherapies reinforcing the host defense against fungi and aiding in clearance of opportunistic pathogens are continuously gaining ground in this battle. Here, we review alternative approaches for the management of fungal infections going beyond the state of the art and placing an emphasis on fungus-specific T cell immunotherapy. Harnessing the power of T cells in the form of adoptive immunotherapy represents the strenuous protagonist of the current immunotherapeutic approaches towards combating invasive fungal infections. The progress that has been made over the last years in this field and remaining challenges as well, will be discussed.

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