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

Abstract

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.

• Authors: Silvia Bellocchio, Roberta Gaziano, Silvia Bozza, Giordano Rossi, Claudia Montagnoli, Katia Perruccio, Mario Calvitti, Lucia Pitzurra, Luigina Romani
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 55 Issue 2 Pg. 214-22 (Feb 2005) ISSN: 0305-7453 [Print] England
• PMID: 15649994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Liposomes
• Receptors, Cell Surface
• Tlr2 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Amphotericin B

Topics

• Amphotericin B (administration & dosage, toxicity)
• Animals
• Antifungal Agents (administration & dosage, toxicity)
• Drug Resistance, Fungal (drug effects, physiology)
• Female
• Humans
• Liposomes
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neutrophils (drug effects, metabolism)
• Receptors, Cell Surface (genetics, metabolism)
• Toll-Like Receptor 2
• Toll-Like Receptor 4