Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Ophthalmology, University of California, Irvine, USA.
Eur J Immunol. 2019 Jun;49(6):918-927. doi: 10.1002/eji.201847851. Epub 2019 May 14.
Aspergillus fumigatus is an important cause of pulmonary and systemic infections in immune compromised individuals, and of corneal ulcers and blindness in immune competent patients. To examine the role of chitin synthases in Aspergillus corneal infection, we analyzed Aspergillus mutants of chitin synthase family 1 and family 2, and found that compared with the parent strain, the quadruple mutants from both families were more readily killed by neutrophils in vitro, and that both also exhibited impaired hyphal growth in the cornea. Further, inhibition of chitin synthases using Nikkomycin Z enhanced neutrophil killing in vitro and in vivo in a murine model of A. fumigatus corneal infection. Acidic mammalian chitinase (AMCase) is mostly produced by macrophages in asthmatic lungs; however, we now demonstrate that neutrophils are a major source of AMCase, which inhibits hyphal growth. In A. fumigatus corneal infection, neutrophils are the major source of AMCase, and addition of AMCase inhibitors or adoptive transfer of neutrophils from AMCase mice resulted in impaired hyphal killing. Together, these findings identify chitin synthases as important fungal virulence factors and neutrophil-derived AMCase as an essential mediator of host defense.
烟曲霉是免疫功能低下个体肺部和全身感染、免疫功能正常患者角膜溃疡和失明的重要原因。为了研究几丁质合酶在烟曲霉角膜感染中的作用，我们分析了几丁质合酶家族 1 和家族 2 的烟曲霉突变体，发现与亲本菌株相比，来自两个家族的四重突变体在体外更易被中性粒细胞杀死，并且在角膜中也表现出菌丝生长受损。此外，使用 Nikkomycin Z 抑制几丁质合酶在烟曲霉菌角膜感染的小鼠模型中增强了中性粒细胞在体外和体内的杀伤作用。酸性哺乳动物几丁质酶 (AMCase) 主要由哮喘肺部的巨噬细胞产生；然而，我们现在证明中性粒细胞是 AMCase 的主要来源，它抑制菌丝生长。在烟曲霉角膜感染中，中性粒细胞是 AMCase 的主要来源，添加 AMCase 抑制剂或从 AMCase 小鼠过继转移中性粒细胞会导致菌丝杀伤受损。综上所述，这些发现确定了几丁质合酶是重要的真菌毒力因子，中性粒细胞衍生的 AMCase 是宿主防御的重要介质。
