ZFIN ID: ZDB-PUB-191120-4
Efficacy of voriconazole against A. fumigatus infection depends on host immune function
Rosowski, E.E., He, J., Huisken, J., Keller, N.P., Huttenlocher, A.
Date: 2019
Source: Antimicrobial Agents and Chemotherapy   64(2): (Journal)
Registered Authors: Huisken, Jan, Huttenlocher, Anna, Rosowski, Emily E.
Keywords: none
MeSH Terms:
  • Animals
  • Antifungal Agents/therapeutic use*
  • Aspergillosis/drug therapy*
  • Aspergillosis/immunology*
  • Aspergillosis/microbiology
  • Aspergillus fumigatus*
  • Immunity, Cellular
  • Larva
  • Macrophages/immunology
  • Microbial Sensitivity Tests
  • Spores, Fungal/immunology
  • Voriconazole/therapeutic use*
  • Zebrafish
PubMed: 31740552 Full text @ Antimicrob. Agents Chemother.
ABSTRACT
Anti-fungal therapy can fail in a remarkable number of patients with invasive fungal disease, resulting in significant morbidity worldwide. A major contributor to this failure is that while these drugs have high potency in vitro, we don't fully understand how they work inside of infected hosts. Here, we used a transparent larval zebrafish model of A. fumigatus infection amenable to real-time imaging of invasive disease as an in vivo intermediate vertebrate model to investigate the efficacy and mechanism of the anti-fungal drug voriconazole. We find that the ability of voriconazole to protect against A. fumigatus infection depends on host innate immune cells, and specifically on the presence of macrophages. While voriconazole inhibits fungal spore germination and growth in vitro, it does not in larval zebrafish. Instead, live imaging of whole, intact larvae over a multi-day course of infection revealed that macrophages slow down initial fungal growth, allowing voriconazole time to target and kill A. fumigatus hyphae post-germination. These findings shed light on how anti-fungal drugs such as voriconazole may synergize with the immune response in living hosts.
ADDITIONAL INFORMATION