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Infection and Immunity, April 2001, p. 2402-2406, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2402-2406.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Involvement of CD14 and Toll-Like Receptors in Activation of Human Monocytes by Aspergillus fumigatus Hyphae

J. E. Wang,1,* A. Warris,2 E. A. Ellingsen,1 P. F. Jørgensen,1 T. H. Flo,3 T. Espevik,3 R. Solberg,4 P. E. Verweij,2 and A. O. Aasen1

Institute for Surgical Research, Rikshospitalet---National Hospital, N-0027 Oslo,1 Department of Pharmacology, School of Pharmacy, University of Oslo, N-0316 Oslo,4 and Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim,3 Norway, and Department of Medical Microbiology, University Medical Center, Nijmegen, The Netherlands2

Received 14 November 2000/Returned for modification 11 December 2000/Accepted 19 January 2001

Invasive fungal infections represent an increasing problem associated with high mortality. The present study was undertaken to identify leukocyte subsets that are activated by hyphal fragments in a whole-human-blood model, as well as to examine the involvement of CD14 and Toll-like receptors (TLRs) in activation of monocytes by hyphae. Incubation of whole human blood with hyphal fragments from Aspergillus fumigatus and Scedosporium prolificans for 6 h caused induction of mRNAs for tumor necrosis factor alpha (TNF-alpha ), interleukin-1beta (IL-1beta ), and IL-6 in T cells, B cells, and monocytes, but not in granulocytes, as analyzed by reverse transcription-PCR with mRNA isolated from very pure populations of these leukocyte subsets. In primary adherent human monocytes, induction of TNF-alpha by hyphal fragments was dependent on plasma. Heat treatment of plasma at 56°C for 30 min strongly reduced the ability of plasma to prime for activation. Pretreatment of human monocytes with different concentrations (1, 3, and 10 µg/ml) of monoclonal antibody (MAb) HTA125 (anti-TLR4) or MAb 18D11 (anti-CD14) for 30 min inhibited the release of TNF-alpha induced by hyphal fragments in a dose-dependent manner. Maximal inhibitions of 35 and 70% were obtained with 10 µg of HTA125 and 18D11 per ml, respectively. In contrast, pretreatment with MAb TL2.1 (anti-TLR2) did not affect signaling induced by hyphae. Pretreatment with the lipid A antagonist B975 blocked lipopolysaccharide signaling but did not inhibit TNF-alpha production induced by hyphal fragments. Our results suggest that T cells, B cells, and monocytes are involved in the innate immune response to invasive fungal pathogens and that serum components are relevant for activation of monocytes by hyphae. CD14 and TLR4 may be involved in signaling of Aspergillus hyphae in monocytes, but further studies to elucidate this issue are warranted.

* Corresponding author. Mailing address: Institute for Surgical Research, Rikshospitalet---National Hospital, Sognsvannsveien 20, N-0027 Oslo, Norway. Phone: 47 23 07 35 20. Fax: 47 23 07 35 30. E-mail: jacob.wang{at}klinmed.uio.no.

Infection and Immunity, April 2001, p. 2402-2406, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2402-2406.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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