Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus

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Abstract

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-α (TNFα) following A. fumigatus stimulation. In contrast, following stimulation with RC, SC, and H, TLR4-/- and CD14-/- macrophages exhibited no defects in tumor necrosis factor-α 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 κ B (NFκB)-dependent reporter gene and greater release of tumor necrosis factor-α from the human monocytic THP-1 cell line stably transfected with CD14 compared with control cells stably transfected with empty vector. A. fumigatus stimulated NFκB-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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Mambula, S. S., Sau, K., Henneke, P., Golenbock, D. T., & Levitz, S. M. (2002). Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus. Journal of Biological Chemistry, 277(42), 39320–39326. https://doi.org/10.1074/jbc.M201683200

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