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Antimicrobial Agents and Chemotherapy, September 2008, p. 3301-3306, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.01018-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Immunomodulatory Effects of Voriconazole on Monocytes Challenged with Aspergillus fumigatus: Differential Role of Toll-Like Receptors

Maria Simitsopoulou,^1,3 Emmanuel Roilides,^1,4 Fotini Paliogianni,² Christodoulos Likartsis,³ John Ioannidis,³ Kalliopi Kanellou,³ and Thomas J. Walsh^4*

Laboratory of Infectious Diseases, 3rd Department of Pediatrics, School of Medicine, Aristotle University, Hippokration Hospital, Thessaloniki 54642, Greece,¹ Department of Microbiology, University of Patras Medical School, Patras 26500, Greece,² Laboratory of Medical Biotechnology, Department of Medical Laboratories, Technological Educational Institute of Thessaloniki, Thessaloniki 57400, Greece,³ Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892⁴

Received 30 July 2007/ Returned for modification 25 January 2008/ Accepted 4 July 2008

Voriconazole (VRC) has activity against Aspergillus fumigatus, the most frequent cause of invasive aspergillosis in immunocompromised patients. The combination of VRC and A. fumigatus hyphae induced a more pronounced profile of expression of genes encoding inflammatory molecules in human monocytes than Aspergillus alone did. Herein, we provide further evidence of the potential mechanism underlying this immunomodulatory effect of VRC on human monocytes in response to A. fumigatus hyphae. A significant additive antifungal effect was shown when VRC was combined with monocytes against A. fumigatus hyphae. Both A. fumigatus hyphae and VRC induced pronounced profiles of mRNA and protein expression of Toll-like receptor 2 (TLR2) as well as tumor necrosis factor alpha (TNF-) in THP-1 monocytic cells compared to untreated cells. The VRC-induced increase was greater than that induced by hyphae. The combination of VRC and hyphae increased mRNA and protein expression of TLR2 and TNF- to even higher levels than did either VRC or hyphae alone. In contrast, TLR4 expression, both at the mRNA and protein levels, was not increased by either VRC or hyphae or their combination. In addition, significantly more NF-B was translocated to the nuclei of THP-1 cells treated with VRC than untreated cells. While VRC induced more NF-B than hyphae did, treatment with the combination of the two factors induced the greatest NF-B expression. The pronounced profile of TLR2 signaling, TNF- expression, and NF-B activation in the presence of VRC suggests an immunomodulatory effect leading to a more efficient response to A. fumigatus.

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* Corresponding author. Mailing address: Pediatric Oncology Branch, National Cancer Institute, Bldg. 10, CRC 1-5750, Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 480-2308. E-mail: walsht{at}mail.nih.gov

Published ahead of print on 14 July 2008.

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Antimicrobial Agents and Chemotherapy, September 2008, p. 3301-3306, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.01018-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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