Schöbel Felicitas, Ibrahim-Granet Oumaïma, Avé Patrick, Latgé Jean-Paul, Brakhage Axel A, Brock Matthias
Leibniz Institute for Natural Products Research and Infection Biology, Beutenbergstr. 11a, 07745 Jena, Germany.
Infect Immun. 2007 Mar;75(3):1237-44. doi: 10.1128/IAI.01416-06. Epub 2006 Dec 18.
Aspergillus fumigatus is the most prevalent airborne filamentous fungus causing invasive aspergillosis in immunocompromised individuals. Only a limited number of determinants directly associated with virulence are known, and the metabolic requirements of the fungus to grow inside a host have not yet been investigated. Previous studies on pathogenic microorganisms, i.e., the bacterium Mycobacterium tuberculosis and the yeast Candida albicans, have revealed an essential role for isocitrate lyase in pathogenicity. In this study, we generated an isocitrate lyase deletion strain to test whether this strain shows attenuation in virulence. Results have revealed that isocitrate lyase from A. fumigatus is not required for the development of invasive aspergillosis. In a murine model of invasive aspergillosis, the wild-type strain, an isocitrate lyase deletion strain, and a complemented mutant strain were similarly effective in killing mice. Moreover, thin sections demonstrated invasive growth of all strains. Additionally, thin sections of lung tissue from patients with invasive aspergillosis stained with anti-isocitrate lyase antibodies remained negative. From these results, we cannot exclude the use of lipids or fatty acids as a carbon source for A. fumigatus during invasive growth. Nevertheless, test results do imply that the glyoxylate cycle from A. fumigatus is not required for the anaplerotic synthesis of oxaloacetate under infectious conditions. Therefore, an antifungal drug inhibiting fungal isocitrate lyases, postulated to act against Candida infections, is assumed to be ineffective against A. fumigatus.
烟曲霉是在免疫功能低下个体中引起侵袭性曲霉病的最常见空气传播丝状真菌。目前已知直接与毒力相关的决定因素数量有限，且该真菌在宿主体内生长的代谢需求尚未得到研究。先前对致病微生物，即结核分枝杆菌和白色念珠菌的研究表明，异柠檬酸裂解酶在致病性中起重要作用。在本研究中，我们构建了一个异柠檬酸裂解酶缺失菌株，以测试该菌株是否表现出毒力减弱。结果表明，烟曲霉的异柠檬酸裂解酶对于侵袭性曲霉病的发展并非必需。在侵袭性曲霉病的小鼠模型中，野生型菌株、异柠檬酸裂解酶缺失菌株和互补突变菌株在杀死小鼠方面同样有效。此外，薄切片显示所有菌株均有侵袭性生长。另外，用抗异柠檬酸裂解酶抗体染色的侵袭性曲霉病患者肺组织薄切片仍为阴性。从这些结果来看，我们不能排除烟曲霉在侵袭性生长过程中使用脂质或脂肪酸作为碳源的可能性。然而，测试结果确实表明，在感染条件下，烟曲霉的乙醛酸循环对于草酰乙酸的回补合成并非必需。因此，一种假定对念珠菌感染起作用的抑制真菌异柠檬酸裂解酶的抗真菌药物，被认为对烟曲霉无效。
