Abstract
Aspergillus fumigatus is a saprophytic fungus that is ubiquitous in the environment and is commonly associated with allergic sensitization and severe asthma in humans. Although A. fumigatus is recognized by multiple microbial pattern-recognition receptors, we found that an A. fumigatus–derived glycosphingolipid, asperamide B, directly activates invariant natural killer T (iNKT) cells in vitro in a CD1d-restricted, MyD88-independent and dectin-1–independent fashion. Moreover, asperamide B, when loaded onto CD1d, directly stained, and was sufficient to activate, human and mouse iNKT cells. In vivo, asperamide B rapidly induced airway hyperreactivity, which is a cardinal feature of asthma, by activating pulmonary iNKT cells in an interleukin-33 (IL-33)-ST2–dependent fashion. Asperamide B is thus the first fungal glycolipid found to directly activate iNKT cells. These results extend the range of microorganisms that can be directly detected by iNKT cells to the kingdom of fungi and may explain how A. fumigatus can induce severe chronic respiratory diseases in humans.
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Change history
27 September 2013
In the version of this article initially published online, the molecular mass of asperamide B was incorrectly given as 738, when it is actually 754. The error has been corrected for the print, PDF and HTML versions of this article.
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Acknowledgements
This work was supported in part by US National Institutes of Health (NIH) grants RO1AI026322, RC1HL099839 and R21AI083523 to D.T.U. and by the Bunning Food Allergy Project to D.T.U. L.A.A. was a graduate student in the Program in Immunology, Division of Medical Sciences, Harvard University. We would also like to acknowledge the NIH National Institute of Allergy and Infectious Diseases (NIAID) research reagent program that provided the A. fumigatus lysates used in this study. We thank the NIH NIAID Tetramer Facility for providing CD1d monomers and tetramers for this study, D.B. Moody for help with plate-bound CD1d assays and M. Grusby (Harvard School of Public Health), M. Taniguchi and T. Nakayama (Chiba University), S. Akira (Osaka University), R. Geha (Boston Children's Hospital) and A. McKenzie (Medical Research Council, Laboratory of Molecular Biology) for providing genetically modified mice.
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L.A.A. conceived and initiated the project, planned and performed experiments and wrote the manuscript. V.C. performed lipid isolation, identification and synthesis. Y.-J.C. planned and performed experiments, including the tetramer studies. H.Y.K. performed experiments and edited the manuscript. Y.-T.C. isolated and maintained iNKT cell lines. M.P. maintained iNKT cell lines, assisted with experiments and provided training in invasive plethysmography. R.H.D. helped plan experiments and edited the manuscript. P.B.S. planned lipid isolation, identification and synthesis and wrote the manuscript. D.T.U. conceived the idea for the project, planned experiments, shepherded the project along and wrote the manuscript.
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Albacker, L., Chaudhary, V., Chang, YJ. et al. Invariant natural killer T cells recognize a fungal glycosphingolipid that can induce airway hyperreactivity. Nat Med 19, 1297–1304 (2013). https://doi.org/10.1038/nm.3321
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DOI: https://doi.org/10.1038/nm.3321
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