JAC Advance Access originally published online on January 13, 2005
Journal of Antimicrobial Chemotherapy 2005 55(2):214-222; doi:10.1093/jac/dkh542
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JAC vol.55 no.2 © The British Society for Antimicrobial Chemotherapy 2005; all rights reserved
Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4
1 Microbiology and 3 Histology Sections, Department of Experimental Medicine and Biochemical Sciences and 2 Division of Hematology, Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
* Corresponding author. Tel/Fax: +39-075-585-741; Email: lromani{at}unipg.it
Objectives: Neutrophils play a crucial role in the control of the Aspergillus fumigatus infection and act in concert with antifungal drugs. This study was undertaken to obtain insights into the possible involvement of Toll-like receptors (TLRs) in the interaction of liposomal amphotericin B (L-AmB; AmBisome) with neutrophils in response to A. fumigatus.
Methods: For generation of bone marrow-transplanted mice, irradiated C57BL6 mice were infused with T cell-depleted allogeneic donor cells. For infection, mice were injected intranasally with Aspergillus fumigatus conidia and treated with L-Amb and deoxycholate amphotericin B prophylactically or therapeutically. For TLR-dependent antifungal functions, murine neutrophils were preincubated with antifungals or TLR ligands before the addition of Aspergillus conidia.
Results: The results show that: (a) neutrophil activation by Aspergillus occurs through TLR signalling pathways differently affecting the oxidative and non-oxidative mechanisms of the killing machinery; (b) by diverting signalling from TLR-2 to TLR-4, liposomes of AmBisome activate neutrophils to an antifungal state while attenuating the pro-inflammatory effects of deoxycholate amphotericin B; (c) this translates in vivo to the optimization of the AmBisome therapeutic efficacy in mice with aspergillosis.
Conclusions: These results provide a putative molecular basis for the reduced infusion-related toxicity of AmBisome and suggest that TLR manipulation in vivo is amenable to the induction of optimal microbicidal activity in the absence of inflammatory cytotoxicity to host cells.
Keywords: AmBisome , Aspergillus fumigatus , neutrophils
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