Abstract
Mammalian cells do not produce chitin, an insoluble polymer of N-acetyl-D-glucosamine (GlcNAc), although chitin is a structural component of the cell wall of pathogenic microorganisms such as Candida albicans. Mammalian cells, including cells of the innate immune system elaborate chitinases, including chitotriosidase (Chit1), which may play a role in the anti-fungal immune response. In the current study, using knockout mice, we determined the role of Chit1 against systemic candidiasis. Chit1-deficient mice showed significant decrease in kidney fungal burden compared to mice expressing the functional enzyme. Using in vitro anti-candidal neutrophil functional assays, the introduction of the Chit1:chitin digestion end-product, chitobiose (N-acetyl-D-glucosamine dimer, GlcNAc2), decreased fungal-induced neutrophil swarming and Candida killing in vitro. Also, a role for the lectin-like binding site on the neutrophil integrin CR3 (Mac-1, CD11b/CD18) was found through physiological competitive interference by chitobiose. Furthermore, chitobiose treatment of wild type mice during systemic candidiasis resulted in the significant increase in fungal burden in the kidney. These data suggest a counterproductive role of Chit1 in mounting an efficient anti-fungal defense against systemic candidiasis.
Highlights
Systemic candidiasis continues to be a significant medical problem in critically ill patients with high morbidity and mortality despite available anti-fungal therapy [1]
Human cells do not produce chitin, they are exposed through contact with chitin containing pathogens including Candida albicans
Of the myriad of known neutrophil specific immunodeficiencies caused by genetic abnormalities linked to Candida infection, including Dectin-1, CD18, CARD9, MPO, and enzymes of the NADPH oxidase pathway [6], to date chitotriosidase has not been linked in an increase in fungal susceptibility [6, 27]
Summary
Systemic candidiasis continues to be a significant medical problem in critically ill patients with high morbidity and mortality despite available anti-fungal therapy [1]. CR3 has two spatially distinct binding sites, the so-called I-domain (binds extracellular matrix) and the lectin-like domain (binds fungal β-glucan), that the simultaneous binding of both sites with ligand results in enhanced anti-microbial cellular responses including neutrophil swarming [9,10,11,12]. Neutrophilic recognition of the fungal pathogen C. albicans causes the release of antimicrobial molecules from granules at the site of fungal infection including the chitin digestion enzyme chitotriosidase (Chit1), which acts on the non-reducing end of the chitin microfibril, Chitotriosidase Activity Counterproductive During Candidiasis releasing copious N-acetyl-D-glucosamine (NADG) dimer, chitobiose, one by one from the chitin chain [13, 14]. Human cells do not produce chitin, they are exposed through contact with chitin containing pathogens including Candida albicans. Recent studies have linked chitotriosidase with anti-Candida activities whether it is necessary to mount an effective anti-fungal inflammatory response has not been sufficiently addressed [14, 16,17,18,19,20]
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