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Aspergillus fumigatus CalA binds to integrin α5β1 and mediates host cell invasion

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Abstract

Aspergillus fumigatus is an opportunistic fungal pathogen that invades pulmonary epithelial cells and vascular endothelial cells by inducing its own endocytosis, but the mechanism by which this process occurs is poorly understood. Here, we show that the thaumatin-like protein CalA is expressed on the surface of the A. fumigatus cell wall, where it mediates invasion of epithelial and endothelial cells. CalA induces endocytosis in part by interacting with integrin α5β1 on host cells. In corticosteroid-treated mice, a ΔcalA deletion mutant has significantly attenuated virulence relative to the wild-type strain, as manifested by prolonged survival, reduced pulmonary fungal burden and decreased pulmonary invasion. Pretreatment with an anti-CalA antibody improves survival of mice with invasive pulmonary aspergillosis, demonstrating the potential of CalA as an immunotherapeutic target. Thus, A. fumigatus CalA is an invasin that interacts with integrin α5β1 on host cells, induces endocytosis and enhances virulence.

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Figure 1: A. fumigatus CalA functions as an invasin.
Figure 2: CalA is required for normal germination and hyphal morphology.
Figure 3: β1 integrin binds to A. fumigatus and is required for maximal endocytosis.
Figure 4: Integrin α5β1 interacts with A. fumigatus CalA.
Figure 5: CalA is required for normal virulence and lung invasion in the mouse model of invasive aspergillosis.
Figure 6: An anti-CalA antibody inhibits host cell invasion and protects mice from lethal invasive aspergillosis.

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  • 14 July 2017

    In the PDF version of this article previously published, the year of publication provided in the footer of each page and in the 'How to cite' section was erroneously given as 2017, it should have been 2016. This error has now been corrected. The HTML version of the article was not affected.

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Acknowledgements

The authors thank D. Villarreal for assistance with tissue culture. This work was supported by National Institutes of Health (NIH) grants R01AI073829 and R56AI111836, by UCLA CTSI grant UL1TR000124 and by operating grants 81361 and 123306 from the Canadian Institutes of Health Research. A.S.I. is supported by NIH grant R01AI063503. D.C.S. is supported by a Chercheur–Boursier Award from the Fonds de Recherche Quebec Santé (FRQS).

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H.L., M.J.L., N.V.S., Q.T.P., A.S.I., D.C.S. and S.G.F. designed the experiments. H.L., M.J.L., N.V.S., Q.T.P., M.S. and B.R. performed the experiments. H.L., M.J.L., D.C.S. and S.G.F. analysed the data. H.L., D.C.S. and S.G.F. wrote the paper.

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Correspondence to Scott G. Filler.

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Ashraf Ibrahim and Scott Filler are co-founders of and hold equity in NovaDigm Therapeutics, Inc.

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Supplementary Tables 1,2, Supplementary Figures 1–14 (PDF 1591 kb)

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Liu, H., Lee, M., Solis, N. et al. Aspergillus fumigatus CalA binds to integrin α5β1 and mediates host cell invasion. Nat Microbiol 2, 16211 (2017). https://doi.org/10.1038/nmicrobiol.2016.211

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