Journal Article

Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4

Silvia Bellocchio, Roberta Gaziano, Silvia Bozza, Giordano Rossi, Claudia Montagnoli, Katia Perruccio, Mario Calvitti, Lucia Pitzurra and Luigina Romani

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 55, issue 2, pages 214-222
Published in print February 2005 | ISSN: 0305-7453
Published online February 2005 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkh542
Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4

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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

Journal Article.  5404 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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