Pulmonary cryptococcosis induces chitinase in the rat.
TL;DR: A possible link between respiratory fungal infections, including C. neoformans, and asthma through the induction of AMCase is indicated through the induced chitinase activity within the lung and bronchoalveolar lavage fluid of infected rats.
Abstract: Background: We previously demonstrated that chronic pulmonary infection with Cryptococcus neoformans results in enhanced allergic inflammation and airway hyperreactivity in a rat model. Because the cell wall of C. neoformans consists of chitin, and since acidic mammalian chitinase (AMCase) has recently been implicated as a novel mediator of asthma, we sought to determine whether such infection induces chitinase activity and expression of AMCase in the rat. Methods: We utilized a previously-established model of chronic C. neoformans pulmonary infection in the rat to analyze the activity, expression and localization of AMCase. Results: Our studies indicate that intratracheal inoculation of C. neoformans induces chitinase activity within the lung and bronchoalveolar lavage fluid of infected rats. Chitinase activity is also elicited by pulmonary infection with other fungi (e.g. C. albicans), but not by the inoculation of dead organisms. Enhanced chitinase activity reflects increased AMCase expression by airway epithelial cells and alveolar macrophages. Systemic cryptococcosis is not associated with increased pulmonary chitinase activity or AMCase expression. Conclusion: Our findings indicate a possible link between respiratory fungal infections, including C. neoformans, and asthma through the induction of AMCase.
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TL;DR: The mechanisms of host chitinase responses may have implications for diagnostic assays as well as novel therapeutic approaches for patients that are at risk of contracting fatal fungal infections.
Abstract: The human immune system is capable of recognizing and degrading chitin, an important cell wall component of pathogenic fungi. In the context of host-immune responses to fungal infections, herein we review the particular contributions and interplay of fungus and chitin recognition, and chitin-degrading enzymes, known as chitinases. The mechanisms of host chitinase responses may have implications for diagnostic assays as well as novel therapeutic approaches for patients that are at risk of contracting fatal fungal infections.
106 citations
Cites background from "Pulmonary cryptococcosis induces ch..."
...neoformans exposure had increased AMCase chitinase activities in the airways [80]....
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TL;DR: It is demonstrated chitosan is necessary for virulence and persistence in the mammalian host in Cryptococcus neoformans.
Abstract: Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningoencephalitis. Its cell wall is composed of glucans, proteins, chitin, and chitosan. Multiple genetic approaches have defined a chitosan-deficient syndrome that includes slow growth and decreased cell integrity. Here we demonstrate chitosan is necessary for virulence and persistence in the mammalian host.
100 citations
Additional excerpts
...tible to host killing and clearance (23)....
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TL;DR: This review covers the recent advances of chitinases as a biocontrol agent and its various applications including preparation of medically important chitooligosaccharides, bioconversion of Chitin as well as in implementing chit inases as diagnostic and prognostic markers for numerous diseases and the prospect of their future utilization.
Abstract: Biological control of phytopathogenic fungi and insects continues to inspire the research and development of environmentally friendly bioactive alternatives. Potentially lytic enzymes, chitinases can act as a biocontrol agent against agriculturally important fungi and insects. The cell wall in fungi and protective covers, i.e. cuticle in insects shares a key structural polymer, chitin, a β-1,4-linked N-acetylglucosamine polymer. Therefore, it is advantageous to develop a common biocontrol agent against both of these groups. As chitin is absent in plants and mammals, targeting its metabolism will signify an eco-friendly strategy for the control of agriculturally important fungi and insects but is innocuous to mammals, plants, beneficial insects and other organisms. In addition, development of chitinase transgenic plant varieties probably holds the most promising method for augmenting agricultural crop protection and productivity, when properly integrated into traditional systems. Recently, human proteins with chitinase activity and chitinase-like proteins were identified and established as biomarkers for human diseases. This review covers the recent advances of chitinases as a biocontrol agent and its various applications including preparation of medically important chitooligosaccharides, bioconversion of chitin as well as in implementing chitinases as diagnostic and prognostic markers for numerous diseases and the prospect of their future utilization.
96 citations
Cites background from "Pulmonary cryptococcosis induces ch..."
...…by Cryptococcus neoformans, well known for its tendency to elicit allergic inflammation and causes persistent sub-clinical pulmonary disease in animal models, suggests that pulmonary cryptococcosis induces endogenous chitinase activity and AMCase expression in rats (Vicencio et al., 2008)....
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...…it has been discovered that chitinases also exist in humans and their role in human diseases has been extensively studied (Bargagli et al., 2007; Boot et al., 1999; Chen et al., 2009; Hollak et al., 1994; Tjoelker, 2000; Vazquez-Torres & Balish, 1997; Vicencio et al., 2008; Zhu et al., 2004)....
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TL;DR: The recent studies in a mouse asthma model revealed that anti-inflammatory drugs like corticosteroid and cysteinyl leukotriene receptor antagonist were able to suppress elevated pulmonary levels of mammalian chitinases, suggesting that mammalian ch itinases may be useful as biomarkers for asthma.
Abstract: Asthma is a chronic inflammatory disease characterized by airway inflammation, mucus hypersecretion and airway hyperresponsiveness. Mechanisms underlying the pathogenesis of asthma are not fully understood. In recent years, there are mounting evidences demonstrating that mammalian chitinases may play a key role in mediating the T-helper 2 cell-driven inflammatory response that is commonly associated with asthma. Chitinases (e.g., chitotriosidase and acidic mammalian chitinase) are enzymes that degrade chitin, the second most abundant biopolymer that can be found in the cell walls of fungi, microfilarial sheaths of helminths, and exoskeletons of insects and crustaceans. There are also chitinase-like proteins (e.g., YKL-40, Ym1 and Ym2) that lack chitinolytic activity but retain chitin-binding ability. Therefore, chitinases were originally believed to function in host defense against parasitic infections, but the first discovery of their role in inflammatory airway diseases came as a surprise. There is ample evidence to support an association of acidic mammalian chitinase and YKL-40 with allergic bronchial asthma in patients. Our recent studies in a mouse asthma model revealed that anti-inflammatory drugs like corticosteroid and cysteinyl leukotriene receptor antagonist were able to suppress elevated pulmonary levels of mammalian chitinases. Taken together, mammalian chitinases may be useful as biomarkers for asthma. Notwithstanding, large-scale multi-center association studies are required to confirm this hypothesis. Besides, substantially more works using knockout mice, recombinant chitinases and siRNA technology are required to investigate a potential role of chitinases in the pathogenesis of asthma.
87 citations
TL;DR: The pathogenesis of C. neoformans from the environment to the brain, the current understanding of the mechanisms of cryptococcal transmission into the brain and cryptococCal meningitis are discussed, and an insight into future cryptococcosis research and the development of novel therapies is given.
Abstract: Brain infection by the fungus Cryptococcus neoformans results in inflammation of the meninges and brain parenchyma, a condition known as meningoencephalitis. One million people are estimated to suffer cryptococcal meningitis globally and >60% of these cases die within 3 months of diagnosis. Humans are believed to contract infection by inhalation of spores or dried yeast cells, which subsequently colonize the lung tissue. In the lungs, cryptococci may be cleared by the lung phagocytes, stay latent, cause pulmonary infection and/or disseminate to other body parts, preferentially the brain, culminating in cryptococcal meningoencephalitis. In this review, we discuss the pathogenesis of C. neoformans from the environment to the brain, the current understanding of the mechanisms of cryptococcal transmission into the brain and cryptococcal meningitis. We also give an insight into future cryptococcosis research and the development of novel therapies.
80 citations
References
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TL;DR: The results suggest a new immunosuppressive effect exerted by glucuronoxylomannan through the induction of IL-10, a potent downregulator of proinflammatory cytokines.
Abstract: In this study, we demonstrated that purified capsular polysaccharide of Cryptococcus neoformans is a potent inducer of interleukin-10 (IL-10) secretion by human monocytes. Endogenous IL-10 was involved in regulating tumor necrosis factor alpha and IL-1beta secretion by human monocytes in response to encapsulated C. neoformans strains. Our results suggest a new immunosuppressive effect exerted by glucuronoxylomannan through the induction of IL-10, a potent downregulator of proinflammatory cytokines.
172 citations
"Pulmonary cryptococcosis induces ch..." refers background in this paper
...The pathogen specific factors that lead to allergic inflammation are not well understood, but several investigators have focused on the role of the cryptococcal polysaccharide [15,16]....
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TL;DR: The present study demonstrates that C. neoformans penetrates the lung parenchyma shortly after infection, immunocompetent rats control pulmonary cryptococcosis efficiently, with minimal extrapulmonary dissemination and low levels of serum GXM; and macrophage activation is likely to play a crucial role in limiting C. Neoformans infection in the rat lung.
Abstract: The pathogenesis of Cryptococcus neoformans pulmonary infection in the rat was studied after intratracheal inoculation. Lungs were examined at various times following infection for histopathology in conjunction with macrophage markers, proliferating cell nuclear antigen (PCNA), and capsular glucuronoxylomannan (GXM) antigen. Serum GXM, immunoglobulin M (IgM) and IgG titers and organ fungal burden were compared with pathological findings. C. neoformans organisms were in the lung parenchyma 2 h postinoculation, and GXM antigen was present in surrounding tissues shortly thereafter. Extrapulmonary dissemination occurred early in infection. Two phases of host cellular inflammatory response were discernible: early local macrophage recruitment at 2 to 4 days followed by granulomatous inflammation, which reached maximum intensity 14 days after infection. The granulomatous phase was preceded by lymphocyte influx with macrophage proliferation and maturation into epithelioid histiocytes; this was paralleled by a shift of yeasts from extracellular to intracellular spaces. Tissue IgG deposits, serum IgG to GXM, and localization of tissue GXM immunoreactivity to epithelioid cells were noted at 2 to 4 weeks. A 10-fold decrease in lung fungal burden occurred 25 days postinfection and was associated with resolving granulomas, fewer proliferating cells, and decreased tissue GXM. The present study demonstrates that (i) C. neoformans penetrates the lung parenchyma shortly after infection; (ii) immunocompetent rats control pulmonary cryptococcosis efficiently, with minimal extrapulmonary dissemination and low levels of serum GXM; and (iii) macrophage activation is likely to play a crucial role in limiting C. neoformans infection in the rat lung.
165 citations
"Pulmonary cryptococcosis induces ch..." refers methods in this paper
...neoformans, American Type Culture Collection (ATCC) strain 24067 was used to establish infection [8]....
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TL;DR: This newly described association between AMCase polymorphisms and asthma adds further evidence supporting the involvement of AMCase in the development of asthma.
Abstract: Rationale: Chitinases are enzymes that cleave chitin, a polysaccharide contained in many parasites of humans. Recent studies in mouse models of bronchial asthma have shown that acid mammalian chitinase (AMCase) is involved in the pathophysiology of asthma. It acts downstream of interleukin-13; inhibition of AMCase leads to an abrogated T-helper cell 2 inflammation, less bronchial hyperreactivity, and fewer eosinophils.
Objectives: The aim of this study was to identify common genetic variants in human AMCase and to use them to test for association of AMCase with pediatric asthma.
Methods: By sequencing the promotor region and all 11 exons on 30 individuals, 12 high-frequency polymorphisms were identified. Genotyping of six variants in exons and one promotor polymorphism was performed on the following populations by means of restriction fragment length polymorphisms: 322 children with asthma, 270 randomly chosen adult controls, and a pediatric control population consisting of 565 children who, at age 10 yr, had never wheezed and never been diagnosed having asthma.
Measurements and Main Results: We identified three known and two new amino acid variants. Analyses by the Armitage's trend test using both control populations showed association of the newly identified variant K17R and the nearby noncoding polymorphism rs3818822 with asthma (p = 0.0031 and p = 0.0003, respectively). In addition, haplotype analyses revealed strong association of haplotypes with the disease (asthma population vs. pediatric control subjects, p < 10−10).
Conclusions: This newly described association between AMCase polymorphisms and asthma adds further evidence supporting the involvement of AMCase in the development of asthma.
134 citations
"Pulmonary cryptococcosis induces ch..." refers background in this paper
...Acidic mammalian chitinase (AMCase) has emerged as an important mediator of allergic asthma in both animal models and in humans [5-7]....
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...Additional investigators have linked human asthma to specific polymorphisms of AMCase [7]....
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TL;DR: In mice, chitotriosidase is expressed only in the gastrointestinal tract, the tongue, fore-stomach, and Paneth cells in the small intestine, whereas in man the enzyme is expressed exclusively by professional phagocytes, which seems to be mediated by distinct promoter usage.
Abstract: Two distinct chitinases have been identified in mammals: a phagocyte-specific enzyme named chitotriosidase and an acidic mammalian chitinase (AMCase) expressed in the lungs and gastrointestinal tract. Increased expression of both chitinases has been observed in different pathological conditions: chitotriosidase in lysosomal lipid storage disorders like Gaucher disease and AMCase in asthmatic lung disease. Recently, it was reported that AMCase activity is involved in the pathogenesis of asthma in an induced mouse model. Inhibition of chitinase activity was found to alleviate the inflammation-driven pathology. We studied the tissue-specific expression of both chitinases in mice and compared it to the situation in man. In both species AMCase is expressed in alveolar macrophages and in the gastrointestinal tract. In mice, chitotriosidase is expressed only in the gastrointestinal tract, the tongue, fore-stomach, and Paneth cells in the small intestine, whereas in man the enzyme is expressed exclusively by prof...
132 citations
"Pulmonary cryptococcosis induces ch..." refers result in this paper
...that increased AMCase expression in airway epithelial cells and alveolar macrophages parallels generalized chitinase activity and is consistent with previous investigations [5,13]....
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TL;DR: Itraconazole modifies the immunologic activation associated with allergic bronchopulmonary aspergillosis and improves clinical outcome, at least over the period of 16 weeks.
Abstract: BACKGROUND Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fumigatus that complicates patients with asthma and cystic fibrosis. The mainstay of treatment for allergic bronchopulmonary aspergillosis remains oral corticosteroids, though this does not completely prevent exacerbations and may not prevent the decline in lung function. OBJECTIVES The purpose of this review was to determine the efficacy of azoles in the treatment of allergic bronchopulmonary aspergillosis. SEARCH STRATEGY We searched the Cochrane Airways Group Asthma trials register using the terms: (allergic bronchopulmonary aspergillosis OR aspergillosis OR allergic pulmonary aspergillosis OR allergic fungal and disease OR allergic mycotic and disease) AND (azole OR triazole OR itraconazole OR ketoconazole). Date of last search January 2003. SELECTION CRITERIA All controlled trials that assessed the effect of azole antifungal agents compared to placebo or other standard therapy for allergic bronchopulmonary aspergillosis were reviewed. Patients with cystic fibrosis were not included. DATA COLLECTION AND ANALYSIS Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS Twelve trials were identified, but only three were prospective, randomised and controlled. A total of 94 participants were included. One demonstrated a reduction in immunological markers of disease activity and symptom scores using ketoconazole 400 mg daily for 12 months. There was no significant improvement in lung function. The other two examined the use of itraconazole for 16 weeks. In one there was a reduction in sputum eosinophils by 35% compared to 19% with placebo (p < 0.01). In the same trial, the number of exacerbations requiring oral corticosteroids was 0.4 per patient with itraconazole compared with 1.3 per patient with placebo (p < 0.03). Meta-analysis of data from both trials showed that itraconazole treated patients were more likely to have decline in serum IgE over 25% or more (Peto OR 3.30; 95% confidence intervals 1.30 to 8.15). REVIEWERS' CONCLUSIONS Itraconazole modifies the immunologic activation associated with allergic bronchopulmonary aspergillosis and improves clinical outcome, at least over the period of 16 weeks. Adrenal suppression with inhaled corticosteroids and itraconazole is a potential concern.
121 citations
"Pulmonary cryptococcosis induces ch..." refers background in this paper
...Fungal infections including Aspergillus fumigatus and dermatophytic infections can exacerbate asthma symptoms in certain patients [1,2]....
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