An immunomodulatory activity of micafungin in preclinical aspergillosis

• Published in: Journal of antimicrobial chemotherapy 2014-04, Vol.69 (4), p.1065-1074
• Main Authors: Moretti, Silvia, Bozza, Silvia, Massi-Benedetti, Cristina, Prezioso, Lucia, Rossetti, Elena, Romani, Luigina, Aversa, Franco, Pitzurra, Lucia
• Format: Article
• Language: English
• Subjects: Animals; Aspergillosis - drug therapy; Aspergillosis - microbiology; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Bacterial Load; Biological activity; Cells, Cultured; Cytokines; Echinocandins - pharmacology; Echinocandins - therapeutic use; Female; Fungal infections; Fungi; Histocytochemistry; Humans; Immunologic Factors - pharmacology; Immunologic Factors - therapeutic use; Inhibitor drugs; Lipopeptides - pharmacology; Lipopeptides - therapeutic use; Lung - microbiology; Lung - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neutrophils - drug effects; Neutrophils - microbiology; Protein expression; Treatment Outcome
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkt457

Objectives Micafungin inhibits 1,3-β-d-glucan synthase and interferes with fungal cell wall synthesis. Clinically, micafungin has been shown to be efficacious for the treatment of invasive fungal infections. However, little is known about the immunomodulatory activity of micafungin in these infections. Methods We evaluated the immunomodulatory activity of escalating doses of micafungin in murine and human polymorphonuclear neutrophils (PMNs) in vitro and in vivo in different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors. Results Micafungin was able to regulate PMN cytokine response to Aspergillus fumigatus conidia by decreasing the expression of tumour necrosis factor-α and increasing that of interleukin-10 (IL-10). In vivo, the therapeutic efficacy of micafungin was strictly dose-dependent, with the maximum activity observed at the highest dose, concomitant with reduced inflammatory pathology. The anti-inflammatory activity of micafungin required IL-10 and occurred through signalling via the TLR2/dectin-1 and TLR3/TRIF pathways. Conclusion Together, these findings suggest that the therapeutic efficacy of micafungin in aspergillosis is orchestrated by the activation of innate immune receptors affecting the inflammatory/anti-inflammatory balance during infection.