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: It is shown that acidic mammalian chitinase (AMCase) is induced via a T helper-2 (Th2)–specific, interleukin-13 (IL-13)–mediated pathway in epithelial cells and macrophages in an aeroallergen asthma model and expressed in exaggerated quantities in human asthma.
Abstract: Chitin is a surface component of parasites and insects, and chitinases are induced in lower life forms during infections with these agents. Although chitin itself does not exist in humans, chitinases are present in the human genome. We show here that acidic mammalian chitinase (AMCase) is induced via a T helper-2 (Th2)-specific, interleukin-13 (IL-13)-mediated pathway in epithelial cells and macrophages in an aeroallergen asthma model and expressed in exaggerated quantities in human asthma. AMCase neutralization ameliorated Th2 inflammation and airway hyperresponsiveness, in part by inhibiting IL-13 pathway activation and chemokine induction. AMCase may thus be an important mediator of IL-13-induced responses in Th2-dominated disorders such as asthma.
795 citations
"Pulmonary cryptococcosis induces ch..." refers background or methods or result 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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...Evidence from their laboratory demonstrates that over-expression of IL-13 induces endogenous AMCase activity and results in airway hyperreactivity [5], and that blockage of AMCase activity attenuates the response....
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...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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...Chitinase activity assay was performed utilizing an established protocol [5]....
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TL;DR: YKL-40 is found in increased quantities in the serum and lungs in a subgroup of patients with asthma, in whom expression of chitinase in both compartments correlates with the severity of asthma.
Abstract: Background The evolutionarily conserved 18-glycosyl-hydrolase family contains true chitinases and chitinase-like proteins that lack enzymatic activity. Acidic mammalian chitinase has recently been associated with animal models of asthma. The related chitinase-like protein, YKL-40 (also called human cartilage glycoprotein 39 [HCgp-39] and chitinase 3–like 1), can be readily measured in the serum. However, its relationship to asthma has not been evaluated. Methods We quantified serum YKL-40 levels in three cohorts of patients with asthma — one recruited from the patient population at Yale University, one from the University of Paris, and one from the University of Wisconsin — as well as in controls from the surrounding communities. In the Paris cohort, immunohistochemical analysis and morphometric quantitation were used to evaluate the locus of expression of YKL-40 in the lung. The clinical characteristics of the patients with high serum or lung YKL-40 levels were also evaluated. Results Serum YKL-40 levels...
525 citations
"Pulmonary cryptococcosis induces ch..." refers background in this paper
...Importantly, additional proteins with chitinase activity have also been discovered in both rodents and humans, including BRP-39 (mouse), YKL-40 (human) and chitotriosidase [17]....
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TL;DR: The study has revealed the existence of a chitinolytic enzyme in the gastrointestinal tract and lung that may play a role in digestion and/or defense.
489 citations
"Pulmonary cryptococcosis induces ch..." refers methods in this paper
...Reactivity at 50 kDa, the approximate molecular weight of AMCase, was used to indicate AMCase expression [9]....
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TL;DR: The results suggest that the low incidence of symptomatic cryptococcal disease in children with AIDS is not a result of lack of exposure to C neoformans, and provide both indirect and direct evidence of C neo formans infection in immunocompetent children.
Abstract: Objective. Cryptococcus neoformans is an important cause of central nervous system infection in adults with acquired immunodeficiency syndrome (AIDS) but an unusual cause of disease in children with AIDS. The basis for this age-related difference in incidence is not known but may be caused by differences in exposure or immune response. The objective of this study was to determine whether the low prevalence of cryptococcal disease among children is related to a lack of exposure to C neoformans . Methods. Sera were obtained from 185 immunocompetent individuals ranging in age from 1 week to 21 years who were being evaluated in an urban emergency department. Sera were analyzed for antibodies to C neoformans and Candida albicans proteins by immunoblotting. Immunoblot patterns were compared with those obtained from sera of patients with cryptococcosis ( n = 10) and workers in a laboratory devoted to the study of C neoformans . The specificity of our results was confirmed by several approaches, including antibody absorption and blocking studies. Sera were also analyzed for the presence of cryptococcal polysaccharide by both enzyme-linked immunosorbent assay and latex agglutination assays. Results. Sera from children 1.1 to 2 years old demonstrated minimal reactivity to C neoformans proteins. In contrast, the majority of sera from children >2 years old recognized many (≥6) C neoformans proteins. For children between 2.1 and 5 years old, 56% of sera ( n = 25) reacted with many proteins, whereas for children >5 years old ( n = 120), 70% of samples reacted with many proteins. Reactivity was decreased by absorbing sera with C neoformans extracts or by preincubating blots with sera from experimentally infected but not from control rats. Reactivity to C neoformans proteins did not correlate with reactivity to C albicans proteins, which was common in sera from children between the ages of 1.1 and 2 years. Cryptococcal polysaccharide was detected at a titer of 1:16 (∼10 ng/mL) in the sera of 1 child, a 5.6-year-old boy who presented to the emergency department with vomiting. Conclusions. Our findings provide both indirect and direct evidence of C neoformans infection in immunocompetent children. Our results indicate that C neoformans infects a majority of children living in the Bronx after 2 years old. These results are consistent with several observations: the ubiquitous nature of C neoformans in the environment, including its association with pigeon excreta; the large number of pigeons in urban areas; and the increased likelihood of environmental exposure for children once they have learned to walk. The signs and symptoms associated with C neoformans infection in immunocompetent children remained to be determined. Primary pulmonary cryptococcosis may be asymptomatic or produce symptoms confused with viral infections and, therefore, not recognized as a fungal infection. Our results suggest that the low incidence of symptomatic cryptococcal disease in children with AIDS is not a result of lack of exposure to C neoformans . These findings have important implications for C neoformans pathogenesis and the development of vaccine strategies.
382 citations
"Pulmonary cryptococcosis induces ch..." refers background in this paper
...neoformans infection is common among Bronx children, a cohort with an extraordinarily high rate of asthma, suggesting a potential role for this type of infection in asthma pathogenesis [4]....
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TL;DR: Despite widespread exposure to household allergens, the strongest relationship between exposure and sensitization was seen in the bedroom and suggested that exposure to low doses of allergen, 2 U/g or less, was a risk factor and that the risk plateaus above 4 U/G.
Abstract: Background: It is important to understand the relationship between environmental allergen exposure dose and the risk of atopic individuals becoming sensitized to that allergen if we are to change the risk of sensitization and morbidity from allergic disease Objective: The objective of these studies was to determine whether there was a dose response between current exposure to mite, cockroach, and cat allergen in inner-city children and to determine the prevalence of sensitization to these allergens Methods: A sample of 500 children was selected from the 1528 children enrolled in the National Cooperative Inner City Asthma Study Children were selected who had a sample of home dust and valid skin test responses performed with a MultiTest skin test device The samples of home dust were collected from the floor and furniture in the kitchen, bedroom, and television/living room and were assayed for Der p 1, Der f 1, Bla g 1, and Fel d 1 allergens Results: Each allergen level correlated significantly between rooms in individual homes Mite (Der p 1 and Der f 1) and cat (Fel d 1) allergen levels were frequently below the detection limit of the assay Cockroach allergen (Bla g 1) concentrations in the child's bedroom were related to the prevalence of positive skin test responses to cockroach allergen extract among the children, with an odds ratio for sensitization of 145 (111-192) Positive skin test responses to cockroach allergen were seen in 15% of children exposed to bedroom dust with a Bla g 1 concentration below the level of detection compared with a rate of 32% in bedrooms with Bla g 1 levels of 1 to 2 U/g and 40% to 44% among those in rooms with 4 U/g or greater The relationship between exposure and positive skin test responses was clearly stronger among atopic children with a greater number of positive skin test responses Conclusions: Despite widespread exposure to household allergens, the strongest relationship between exposure and sensitization was seen in the bedroom The dose response between exposure to cockroach allergen and sensitization suggested that exposure to low doses of allergen, 2 U/g or less, was a risk factor and that the risk plateaus above 4 U/g Atopy modified the relationship of exposure to sensitization (J Allergy Clin Immunol 1998;102:563-70)
328 citations
"Pulmonary cryptococcosis induces ch..." refers background in this paper
...We also note that chitin is also major constituent of other exposures that have been linked with urban asthma including cockroaches [19]....
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