Aspergillus fumigatus is a major opportunistic human pathogen. Multiple traits contribute to A. fumigatus pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate A. fumigatus virulence. The genome of Aspergillus fischeri, a very close nonpathogenic relative of A. fumigatus, contains a biosynthetic gene cluster that is homologous to the A. fumigatus gliotoxin cluster. However, A. fischeri is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen A. fumigatus and the nonpathogen A. fischeri, we examined whether A. fischeri strain NRRL 181 biosynthesizes gliotoxin and whether the production of secondary metabolites influences the virulence profile of A. fischeri We found that A. fischeri biosynthesizes gliotoxin under the same conditions as A. fumigatus However, whereas loss of laeA, a master regulator of secondary metabolite production (including gliotoxin biosynthesis), has previously been shown to reduce A. fumigatus virulence, we found that laeA loss (and loss of secondary metabolite production) in A. fischeri does not influence its virulence. These results suggest that LaeA-regulated secondary metabolites are virulence factors in the genomic and phenotypic background of the major pathogen A. fumigatus but are much less important in the background of the nonpathogen A. fischeri Understanding the observed spectrum of pathogenicity across closely related pathogenic and nonpathogenic Aspergillus species will require detailed characterization of their biological, chemical, and genomic similarities and differences.IMPORTANCE Aspergillus fumigatus is a major opportunistic fungal pathogen of humans, but most of its close relatives are nonpathogenic. Why is that so? This important, yet largely unanswered, question can be addressed by examining how A. fumigatus and its close nonpathogenic relatives are similar or different with respect to virulence-associated traits. We investigated whether Aspergillus fischeri, a nonpathogenic close relative of A. fumigatus, can produce gliotoxin, a mycotoxin known to contribute to A. fumigatus virulence. We discovered that the nonpathogenic A. fischeri produces gliotoxin under the same conditions as those of the major pathogen A. fumigatus However, we also discovered that, in contrast to what has previously been observed in A. fumigatus, the loss of secondary metabolite production in A. fischeri does not alter its virulence. Our results are consistent with the "cards of virulence" model of opportunistic fungal disease, in which the ability to cause disease stems from the combination ("hand") of virulence factors ("cards") but not from individual factors per se.

中文翻译：

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胶质毒素是主要的人类病原体烟曲霉中的一种已知毒力因子，其非致病性相对费氏曲霉也可以生物合成。

烟曲霉是主要的机会性人类病原体。多种性状有助于烟曲霉的致病性，包括其产生特定次生代谢产物（例如gliotoxin）的能力。已知胶质毒素会抑制宿主的免疫反应，而使胶质毒素生物合成失活的基因突变体（或一般而言是次级代谢）会减弱烟曲霉的毒力。烟曲霉是烟曲霉的非常近的非致病亲缘种，其基因组包含与烟曲霉胶质毒素簇同源的生物合成基因簇。但是，未知费氏曲霉会产生胶质毒素。为了进一步了解主要病原体烟曲霉和非病原体费氏曲霉之间的异同，我们检查了是否 fischeri菌株NRRL 181可生物合成胶质毒素以及次级代谢产物的产生是否会影响A. fischeri的毒力谱我们发现，A。fischeri可在与烟曲霉相同的条件下生物合成胶质毒素。以前已经证明，其生产（包括神经毒素的生物合成）可以降低烟曲霉的毒力，我们发现费氏曲霉的laeA损失（和次级代谢产物的损失）不会影响其毒力。这些结果表明，在主要病原体烟曲霉的基因组和表型背景下，LaeA调控的次生代谢产物是致病因子，但在非病原体A的背景下重要性较低。fischeri要了解在密切相关的致病性和非致病性曲霉物种中观察到的致病谱，就需要对其生物学，化学和基因组相似性和差异进行详细的表征。非致病性的。为什么呢？通过检查烟曲霉及其近亲非致病亲戚在毒力相关性状上如何相似或不同，可以解决这个重要但仍未得到解答的问题。我们调查了曲霉曲霉，烟曲霉的非致病性近亲，是否可以产生葡聚糖毒素，一种已知会导致烟曲霉毒力的霉菌毒素。我们发现非致病性A。费氏菌在与主要病原体烟曲霉相同的条件下产生胶体毒素。但是，我们还发现，与以前在烟曲霉中观察到的相反，费氏菌次生代谢产物的产生并没有改变毒力。我们的结果与机会性真菌疾病的“毒力卡”模型相一致，在该模型中，致病能力来自毒力因子（“卡”）的组合（“手”），而不是源于个别因素本身。