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Infection and Immunity, May 2008, p. 2123-2129, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.00047-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 9-Dependent Immune Activation by Unmethylated CpG Motifs in Aspergillus fumigatus DNA{triangledown} ,{dagger}

Zaida G. Ramirez-Ortiz,1 Charles A. Specht,1 Jennifer P. Wang,1 Chrono K. Lee,1 Daniella C. Bartholomeu,2 Ricardo T. Gazzinelli,1,2 and Stuart M. Levitz1*

Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, Massachusetts,1 Departamento de Parasitologia e Departamento de Bioquímica e Imunologia, ICB, UFMG, Belo Horizonte, Minas Gerais, Brazil2

Received 13 January 2008/ Returned for modification 18 February 2008/ Accepted 27 February 2008

Phagocytic defenses are critical for effective host defenses against the opportunistic fungal pathogen Aspergillus fumigatus. Previous studies found that following challenge with A. fumigatus, Toll-like receptor 9 (TLR9) knockout mice survived longer than wild-type mice. However, the mechanism responsible was not defined. Here we demonstrate that A. fumigatus contains unmethylated CpG sequences, the natural ligands for TLR9. A. fumigatus DNA and synthetic CpG-rich oligodeoxynucleotides (ODNs) containing sequences found in the A. fumigatus genome potently stimulated the production of proinflammatory cytokines in mouse bone marrow-derived dendritic cells (BMDCs) and human plasmacytoid dendritic cells. The response was decreased when the fungal DNA was treated with a CpG methylase or with CpG-specific endonucleases. A role for TLR9 was demonstrated as cytokine production was abolished in BMDCs from TLR9-deficient mice. Moreover, transfection of HEK293 cells with human TLR9 conferred responsiveness to synthetic CpG-rich ODNs containing sequences found in A. fumigatus DNA. Taken together, these data demonstrate that TLR9 detects A. fumigatus DNA, resulting in the secretion of proinflammatory cytokines, which may contribute to the immune response to the pathogen.

* Corresponding author. Mailing address: 364 Plantation Street, LRB317, Worcester, MA 01605. Phone: (508) 856-1525. Fax: (508) 856-1828. E-mail: stuart.levitz{at}umassmed.edu

{triangledown} Published ahead of print on 10 March 2008.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. Casadevall

Infection and Immunity, May 2008, p. 2123-2129, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.00047-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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