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J. Biol. Chem., Vol. 277, Issue 42, 39320-39326, October 18, 2002

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Toll-like Receptor (TLR) Signaling in Response to Aspergillus fumigatus^*

Salamatu S. Mambula^§, Keya Sau, Philipp Henneke^¶, Douglas T. Golenbock^¶, and Stuart M. Levitz^**

From the  Evans Memorial Department of Clinical Research, Departments of Medicine and Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118 and the ^¶ Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Aspergillus fumigatus causes life-threatening infections in patients with qualitative and quantitative defects in phagocytic function. Here, we examined the contribution of Toll-like receptor (TLR)-2, TLR4, the adapter protein MyD88, and CD14 to signaling in response to the three forms of A. fumigatus encountered during human disease: resting conidia (RC), swollen conidia (SC), and hyphae (H). Compared with elicited peritoneal macrophages obtained from wild-type and heterozygous mice, TLR2^/ and MyD88^/ macrophages produced significantly less tumor necrosis factor- (TNF) following A. fumigatus stimulation. In contrast, following stimulation with RC, SC, and H, TLR4^/ and CD14^/ macrophages exhibited no defects in tumor necrosis factor- release. TLR2^/, TLR4^/, MyD88^/, and CD14^/ macrophages bound similar numbers of RC and SC compared with wild-type macrophages. RC, SC, and H stimulated greater activation of a nuclear factor  B (NFB)-dependent reporter gene and greater release of tumor necrosis factor- from the human monocytic THP-1 cell line stably transfected with CD14 compared with control cells stably transfected with empty vector. A. fumigatus stimulated NFB-dependent reporter gene activity in the human embryonic kidney cell line, HEK293, only if the cells were transfected with TLR2. Moreover, activity increased when TLR2 and CD14 were co-transfected. Taken together, these data suggest that optimal signaling responses to A. fumigatus require TLR2 in both mouse and human cells. In contrast, a role for CD14 was found only in the human cells. MyD88 acts as a central adapter protein mediating signaling responses following stimulation with RC, SC, and H.

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