Spikes Sara, Xu Ran, Nguyen C Kim, Chamilos Georgios, Kontoyiannis Dimitrios P, Jacobson Raymond H, Ejzykowicz Daniele E, Chiang Lisa Y, Filler Scott G, May Gregory S
Division of Pathology and Laboratory Medicine, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
J Infect Dis. 2008 Feb 1;197(3):479-86. doi: 10.1086/525044.
Gliotoxin is a epipolythiodioxopiperazine toxin that is made by the filamentous fungus Aspergillus fumigatus. Gliotoxin has a wide range of effects on metazoan cells in culture, including induction of apoptosis through inhibition of Nf-kappaB, and inhibition of superoxide production by phagocytes. These activities have led to the proposal that gliotoxin contributes to pathogenesis during invasive aspergillosis. We tested this hypothesis by creating isogenic strains of gliotoxin-producing and nonproducing strains.
We deleted gliP, the gene that encodes the nonribosomal peptide synthetase GliP. GliP catalyzes the first biosynthetic step in the synthesis of gliotoxin. We then tested for gliotoxin production and virulence in different animal models.
Deletion of gliP resulted in strains that were wild type for growth, but they did not synthesize gliotoxin. Transformation of gliP deletion mutants with a full copy of gliP restored gliotoxin production. The gliP deletion strain had attenuated virulence in nonneutropenic mice immunosuppressed with corticosteroids, but had normal virulence in neutropenic mice. It also had reduced virulence in a Drosophila melanogaster model.
Gliotoxin only contributes to the virulence of A. fumigatus in nonneutropenic mice and in fruit flies with functional phagocytes. These results suggest that the principal targets of gliotoxin are neutrophils or other phagocytes.
Gliotoxin是一种由丝状真菌烟曲霉产生的表硫代二氧哌嗪毒素。Gliotoxin对培养中的后生动物细胞具有广泛影响，包括通过抑制核因子κB诱导细胞凋亡，以及抑制吞噬细胞产生超氧化物。这些活性促使人们提出Gliotoxin在侵袭性曲霉病发病机制中起作用的观点。我们通过构建产生Gliotoxin和不产生Gliotoxin的同基因菌株来验证这一假设。
我们删除了编码非核糖体肽合成酶GliP的gliP基因。GliP催化Gliotoxin合成的第一步生物合成反应。然后我们在不同动物模型中检测Gliotoxin的产生和毒力。
删除gliP导致菌株生长表现为野生型，但它们不合成Gliotoxin。用完整的gliP拷贝转化gliP缺失突变体可恢复Gliotoxin的产生。gliP缺失菌株在用皮质类固醇免疫抑制的非中性粒细胞减少小鼠中毒力减弱，但在中性粒细胞减少小鼠中具有正常毒力。它在果蝇模型中的毒力也降低。
Gliotoxin仅在非中性粒细胞减少小鼠和具有功能性吞噬细胞的果蝇中对烟曲霉的毒力有贡献。这些结果表明Gliotoxin的主要靶标是中性粒细胞或其他吞噬细胞。
