Impaired host defense against Sporothrix schenckii in mice with chronic granulomatous disease.
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ABSTRACT:
SUBMITTER: Kajiwara H
PROVIDER: S-EPMC517470 | biostudies-other | 2004 Sep
REPOSITORIES: biostudies-other
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Project description:Chronic granulomatous disease (CGD) patients have recurrent life-threatening bacterial and fungal infections. Olfactomedin 4 (OLFM4) is a neutrophil granule protein that negatively regulates host defense against bacterial infection. The goal of this study was to evaluate the impact of Olfm4 deletion on host defense against Staphylococcus aureus and Aspergillus fumigatus in a murine X-linked gp91phox-deficiency CGD model. We found that intracellular killing and in vivo clearance of S. aureus, as well as resistance to S. aureus sepsis, were significantly increased in gp91phox and Olfm4 double-deficient mice compared with CGD mice. The activities of cathepsin C and its downstream proteases (neutrophil elastase and cathepsin G) and serum levels of IL-1?, IL-6, IL-12p40, CXCL2, G-CSF, and GM-CSF in Olfm4-deficient as well as gp91phox and Olfm4 double-deficient mice were significantly higher than those in WT and CGD mice after challenge with S. aureus. We did not observe enhanced defense against A. fumigatus in Olfm4-deficient mice using a lung infection model. These results show that Olfm4 deletion can successfully enhance immune defense against S. aureus, but not A. fumigatus, in CGD mice. These data suggest that OLFM4 may be an important target in CGD patients for the augmentation of host defense against bacterial infection.
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Project description:Chronic granulomatous disease (CGD) is a paradigm for nonlymphoid primary immune defects, and has guided elucidation of oxygen metabolism in the phagocyte, vasculature, and brain. It has been in the forefront of the development of antimicrobial prophylaxis before the advent of advanced HIV and before its routine use in neutropenia. It has been an attractive target for gene therapy and bone marrow transplantation for nonmalignant diseases. Therefore, CGD is worthy of attention for its historical interest and because it is a disease for which expert management is imperative.
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Project description:IntroductionChronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent, life-threatening bacterial and fungal infections of the skin, the airways, the lymph nodes, the liver, the brain and the bones. Frequently found pathogens are Staphylococcus aureus, Aspergillus species, Klebsiella species, Burkholderia cepacia, Serratia marcescens and Salmonella species.Sources of dataCGD is a rare (∼1:250 000 individuals) disease caused by mutations in any one of the five components of the NADPH oxidase in phagocytic leucocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes.Areas of agreementCGD patients suffer not only from life-threatening infections, but also from excessive inflammatory reactions.Areas of controversyNeither the cause of these inflammatory reactions nor the way to treat them is clear.Areas timely for developing researchPatient selection for and timing of bone marrow transplantation along with gene therapy.
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Project description:Human exposure to carbon nanotubes (CNT) has been associated with the development of pulmonary sarcoid-like granulomatous disease. Our previous studies demonstrated that multi-walled carbon nanotubes (MWCNT) induced chronic pulmonary granulomatous inflammation in mice. Granuloma formation was accompanied by decreased peroxisome proliferator-activated receptor gamma (PPARγ) and disrupted intracellular lipid homeostasis in alveolar macrophages. Others have shown that PPARγ activation increases mitochondrial fatty acid oxidation (FAO) to reduce free fatty acid accumulation. Hence, we hypothesized that the disrupted lipid metabolism suppresses mitochondrial FAO. To test our hypothesis, C57BL/6 J mice were instilled by an oropharyngeal route with 100 μg MWCNT freshly suspended in 35 % Infasurf. Control sham mice received vehicle alone. Sixty days following instillation, mitochondrial FAO was measured in permeabilized bronchoalveolar lavage (BAL) cells. MWCNT instillation reduced the mitochondrial oxygen consumption rate of BAL cells in the presence of palmitoyl-carnitine as mitochondrial fuel. MWCNT also reduced mRNA expression of mitochondrial genes regulating FAO, carnitine palmitoyl transferase-1 (CPT1), carnitine palmitoyl transferase-2 (CPT2), hydroxyacyl-CoA dehydrogenase subunit beta (HADHB), and PPARγ coactivator 1 alpha (PPARGC1A). Importantly, both oxidative stress and apoptosis in alveolar macrophages and lung tissues of MWCNT-instilled mice were increased. Because macrophage PPARγ expression has been reported to be controlled by miR-27b which is known to induce oxidative stress and apoptosis, we measured the expression of miR-27b. Results indicated elevated levels in alveolar macrophages from MWCNT-instilled mice compared to controls. Given that inhibition of FAO and apoptosis are linked to M1 and M2 macrophage activation, respectively, the expression of both M1 and M2 key indicator genes were measured. Interestingly, results showed that both M1 and M2 phenotypes of alveolar macrophages were activated in MWCNT-instilled mice. In conclusion, alveolar macrophages of MWCNT-instilled mice had increased miR-27b expression, which may reduce the expression of PPARγ resulting in attenuation of FAO. This reduction in FAO may lead to activation of M1 macrophages. The upregulation of miR-27b may also induce apoptosis, which in turn can cause M2 activation of alveolar macrophages. These observations indicate a possible role of miR-27b in impaired mitochondrial function in the chronic activation of alveolar macrophages by MWCNT and the development of chronic pulmonary granulomatous inflammation.
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Project description:Polymorphonuclear leukocytes (PMNs) were obtained from healthy individuals (Healthy1, Healthy2, Healthy3, and Healthy4) or patients with X-linked chronic granulomatous disease (XCGD1, XCGD2, XCGD3, XCGD4, XCGD5, and XCGD6). The studies were performed in accordance with a protocol approved by the Institutional Review Board for Human Subjects, National Institute of Allergy and Infectious Diseases, and the Institutional Review Board for Human Subjects at the University of Iowa. All studies were conducted according to Declaration of Helsinki principles. PMNs (107) were combined with or without IgG and C3bi-coated latex beads (8 x 107) in wells of a 12-well tissue culture plate (pre-coated with 20% normal human serum) and centrifuged at 350 x g for 8 min at 4oC to synchronize phagocytosis. For the purpose of these studies, activated or "Stimulated" PMNs are defined as those that have been stimulated by phagocytosis of IgG- and C3bi-coated latex beads. "Control" PMNs are defined as resting cells or those left unstimulated throughout the time-course. Following centrifugation, plates were incubated at 37 deg. C in a CO2 for the indicated times. At the indicated times, tissue culture medium was aspirated from the plate and PMNs were lysed directly with RLT buffer (Qiagen, Valencia, CA). Purification of PMN RNA and subsequent preparation of labeled cRNA target (12 g) was performed as described in Methods. Labeling of samples, hybridization of cRNA with Hu95Av2 oligonucleotide arrays (Affymetrix, Santa Clara, CA), and scanning were performed according to standard Affymetrix protocols. Gene expression in healthy control and XCGD individuals was always compared at the same time points after phagocytosis Keywords = HUMAN PMN CHRONIC GRANULOMATOUS DISEASE NEUTROPHILS Keywords: parallel sample
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Project description:The increase in levels of cAMP in leukocytes by selective inhibitors of PDE4 may result in reduction of inflammation, and may be useful in the treatment of pulmonary inflammatory disorders in humans. Here, we have assessed whether oral treatment with the prototype PDE4 inhibitor, rolipram, interfered with the antibacterial host response following pulmonary infection of mice with Klebsiella pneumoniae. K. pneumoniae infection induced a marked increase in the recruitment of neutrophils to the lungs and the production of proinflammatory cytokines and chemokines, including tumor necrosis factor-alpha (TNF-alpha) and keratinocyte-derived chemokine (KC), in bronchoalveolar (BAL) fluid and lung tissue. There were also detectable amounts of interleukin-10 (IL-10) and significant lethality. Treatment with rolipram (3-30 mg kg-1) was associated with earlier lethality and significant inhibition of the TNF-alpha production. This was associated with enhanced production of IL-10 in lung tissue of rolipram-treated animals. Rolipram treatment did not affect KC expression and the recruitment of neutrophils in the lung tissue. Over 70% of neutrophils that migrated into the BAL fluid following K. pneumoniae infection ingested bacteria. Treatment with rolipram inhibited the percentage of neutrophils undergoing phagocytosis of K. pneumoniae in a dose-dependent manner. Maximal inhibition (62%) occurred at doses equal to or greater than 10 mg kg-1. Thus, treatment of mice with the PDE4 inhibitor rolipram is accompanied by earlier lethality, enhanced bacterial load and decreased capacity of the responding host to produce TNF-alpha and of neutrophils to phagocytose bacteria. It will be important to investigate whether the shown ability of PDE4 inhibitors to inhibit neutrophil phagocytosis and control experimental bacterial infection will translate into an inhibition of the ability of neutrophils to deal with infectious microorganisms in the clinical setting.
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Participants are divided into patients with IBD symptoms (Group 1) and patients without IBD symptoms (Group 2) for the following procedures:
Group 1
Patients are evaluated every 6 months with a medical history and physical examination for signs and symptoms of IBD. Patients who are taking moderate to high doses of steroid medications have their medication slowly lowered (tapered) and are evaluated every 3 months for a total of 2 years. Patients in this group who start to develop IBD symptoms are moved to Group 2 for treatment with infliximab (see below).
Group 2
Patients in Group 2 receive infliximab infusions at 2-week intervals for three doses. The drug is given over a 2-hour period through a catheter placed in a vein. Patients are evaluated with a medical history, physical exam, and blood tests the day of each dose. One week after the last dose, they have another evaluation, including a colonoscopy. Patients who respond well to infliximab may continue to receive the drug every 2 months for a total of 1 year, with evaluations at every dosing visit. At the end of the first year of receiving infliximab, all patients have follow-up evaluations every 6 months for a total of 2 years.
Group 3
Subjects who volunteer to undergo colonoscopy and research biopsies that serve as controls for evaluation of the patient gut samples.
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