Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.
mBio. 2020 Feb 11;11(1):e03361-19. doi: 10.1128/mBio.03361-19.
is a major opportunistic human pathogen. Multiple traits contribute to 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 virulence. The genome of , a very close nonpathogenic relative of , contains a biosynthetic gene cluster that is homologous to the gliotoxin cluster. However, is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen and the nonpathogen , we examined whether strain NRRL 181 biosynthesizes gliotoxin and whether the production of secondary metabolites influences the virulence profile of We found that biosynthesizes gliotoxin under the same conditions as However, whereas loss of , a master regulator of secondary metabolite production (including gliotoxin biosynthesis), has previously been shown to reduce virulence, we found that loss (and loss of secondary metabolite production) in 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 but are much less important in the background of the nonpathogen Understanding the observed spectrum of pathogenicity across closely related pathogenic and nonpathogenic species will require detailed characterization of their biological, chemical, and genomic similarities and differences. 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 and its close nonpathogenic relatives are similar or different with respect to virulence-associated traits. We investigated whether , a nonpathogenic close relative of , can produce gliotoxin, a mycotoxin known to contribute to virulence. We discovered that the nonpathogenic produces gliotoxin under the same conditions as those of the major pathogen However, we also discovered that, in contrast to what has previously been observed in , the loss of secondary metabolite production in 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 .
是一种主要的机会性人类病原体。多种特征导致其致病性，包括产生特定次生代谢物的能力，如 gliotoxin。已知 gliotoxin 抑制宿主免疫反应，失活 gliotoxin 生物合成（或一般次生代谢）的遗传突变体减弱了毒力。非常接近的非致病性近缘种 的基因组包含一个与 gliotoxin 簇同源的生物合成基因簇。然而， 并不已知产生 gliotoxin。为了更深入地了解主要病原体 和非病原体 之间的相似和不同之处，我们检查了 菌株 NRRL 181 是否生物合成 gliotoxin，以及次生代谢物的产生是否影响 的毒力特征。我们发现 在与 相同的条件下生物合成 gliotoxin。然而，先前已经表明，次级代谢产物产生的主要调控因子 的缺失（包括 gliotoxin 生物合成）降低了 的毒力，而我们发现 在 中的缺失（和次生代谢产物产生的缺失）并不影响其毒力。这些结果表明，LaeA 调控的次生代谢物是主要病原体 基因组和表型背景中的毒力因子，但在非病原体 的背景中则不那么重要。了解密切相关的致病性和非致病性 种之间观察到的致病性谱需要详细描述它们在生物学、化学和基因组方面的相似和不同之处。 是人类的一种主要机会性真菌病原体，但它的大多数近缘种都是非致病性的。为什么会这样？通过检查 和其密切的非致病性近缘种在与毒力相关的特征上是相似还是不同，可以解决这个重要但尚未得到充分解答的问题。我们研究了非致病性近缘种 是否可以产生 gliotoxin，一种已知有助于 毒力的真菌毒素。我们发现，非致病性 在与主要病原体 相同的条件下产生 gliotoxin。然而，我们也发现，与以前在 中观察到的情况相反， 中次生代谢产物产生的缺失并不改变其毒力。我们的结果与机会性真菌病的“毒力牌”模型一致，在该模型中，疾病的发生源于毒力因子（“牌”）的组合（“手牌”），而不是单个因子。
