Department of Biological Sciences, Clemson University, Clemson, South Carolina, USA
Morgridge Institute for Research, Madison, Wisconsin, USA.
Antimicrob Agents Chemother. 2020 Jan 27;64(2). doi: 10.1128/AAC.00917-19.
Antifungal 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 , we do not fully understand how they work inside infected hosts. Here, we used a transparent larval zebrafish model of infection amenable to real-time imaging of invasive disease as an intermediate vertebrate model to investigate the efficacy and mechanism of the antifungal drug voriconazole. We found that the ability of voriconazole to protect against infection depends on host innate immune cells and, specifically, on the presence of macrophages. While voriconazole inhibits fungal spore germination and growth , it does not do so in larval zebrafish. Instead, live imaging of whole, intact larvae over a multiday course of infection revealed that macrophages slow down initial fungal growth, allowing voriconazole time to target and kill hyphae postgermination. These findings shed light on how antifungal drugs such as voriconazole may synergize with the immune response in living hosts.
抗真菌治疗在许多侵袭性真菌感染患者中会失败，导致全球范围内发病率显著增加。导致这种失败的一个主要原因是，虽然这些药物具有很高的效力，但我们并不完全了解它们在感染宿主体内的作用机制。在这里，我们使用了一种透明的幼虫斑马鱼感染模型，该模型适合实时成像侵袭性疾病，作为一种中间脊椎动物模型，研究了抗真菌药物伏立康唑的疗效和作用机制。我们发现，伏立康唑预防感染的能力取决于宿主固有免疫细胞，特别是巨噬细胞。虽然伏立康唑抑制真菌孢子的萌发和生长，但在幼虫斑马鱼中并非如此。相反，在整个幼虫感染过程中进行多天的实时成像显示，巨噬细胞减缓了初始真菌的生长速度，使伏立康唑有时间在孢子萌发后靶向并杀死菌丝。这些发现揭示了抗真菌药物（如伏立康唑）如何与活体宿主的免疫反应协同作用。
