Chang Y C, Segal B H, Holland S M, Miller G F, Kwon-Chung K J
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Clin Invest. 1998 May 1;101(9):1843-50. doi: 10.1172/JCI2301.
Chronic granulomatous disease (CGD) is a rare genetic disorder in which phagocytes fail to produce superoxide because of defects in one of several components of the NADPH oxidase complex. As a result, patients develop recurrent life-threatening bacterial and fungal infections. The organisms to which CGD patients are most susceptible produce catalase, regarded as an important factor for microbial pathogenicity in CGD. To test the role of pathogen-derived catalase in CGD directly, we have generated isogenic strains of Aspergillus nidulans in which one or both of the catalase genes (catA and catB), have been deleted. We hypothesized that catalase negative mutants would be less virulent than the wild-type strain in experimental animal models. CGD mice were produced by disruption of the p47(phox) gene which encodes the 47-kD subunit of the NADPH oxidase. Wild-type A. nidulans inoculated intranasally caused fatal infection in CGD mice, but did not cause disease in wild-type littermates. Surprisingly, wild-type A. nidulans and the catA, catB, and catA/catB mutants were equally virulent in CGD mice. Histopathological studies of fatally infected CGD mice showed widely distributed lesions in the lungs regardless of the presence or absence of the catA and catB genes. Similar to the CGD model, catalase-deficient A. nidulans was highly virulent in cortisone-treated BALB/c mice. Taken together, these results indicate that catalases do not play a significant role in pathogenicity of A. nidulans in p47(phox)-/- mice, and therefore raise doubt about the central role of catalases as a fungal virulence factor in CGD.
慢性肉芽肿病（CGD）是一种罕见的遗传性疾病，由于烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶复合物的几个组成部分之一存在缺陷，吞噬细胞无法产生超氧化物。因此，患者会反复发生危及生命的细菌和真菌感染。CGD患者最易感染的病原体可产生过氧化氢酶，这被认为是CGD中微生物致病性的一个重要因素。为了直接测试病原体来源的过氧化氢酶在CGD中的作用，我们构建了构巢曲霉的同基因菌株，其中一个或两个过氧化氢酶基因（catA和catB）已被删除。我们假设在实验动物模型中，过氧化氢酶阴性突变体的毒力会低于野生型菌株。通过破坏编码NADPH氧化酶47-kD亚基的p47（phox）基因制备了CGD小鼠。经鼻接种野生型构巢曲霉可导致CGD小鼠发生致命感染，但在野生型同窝小鼠中不引起疾病。令人惊讶的是，野生型构巢曲霉以及catA、catB和catA/catB突变体在CGD小鼠中的毒力相同。对致命感染的CGD小鼠进行的组织病理学研究表明，无论是否存在catA和catB基因，肺部均有广泛分布的病变。与CGD模型相似，过氧化氢酶缺陷型构巢曲霉在经可的松处理的BALB/c小鼠中具有高毒力。综上所述，这些结果表明过氧化氢酶在p47（phox）-/-小鼠中对构巢曲霉的致病性不起重要作用，因此对过氧化氢酶作为CGD中真菌毒力因子的核心作用提出了质疑。
