Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant
Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant
复制标题
DOI：
10.1128/iai.01124-15
复制
发表时间：
2016-04-01
影响因子：
3.1
通讯作者：
Krappmann, Sven
中科院分区：
文献类型：
--
作者：
Amich, Jorge;Duemig, Michaela;Krappmann, Sven
由于免疫功能低下患者数量的增加，经常延迟诊断和有限的治疗方法，真菌感染具有重要意义。迄今为止，真菌在感染过程中的生长和营养需求，这是相关的入侵宿主，知之甚少。这对于侵袭性肺曲霉病尤其如此，因为到目前为止，在感染期间利用的（宏）元素的来源仅在有限程度上被确定。在这里，我们调查了硫（S）的利用人类致病性霉菌烟曲霉在侵入性生长。我们的数据表明，无机S化合物或牛磺酸是不可能作为S源在侵袭性肺曲霉菌病，因为硫酸盐转运蛋白突变株和亚硫酸盐还原酶突变株是完全有毒的。相反，含S氨基酸半胱氨酸限制真菌生长，如半胱氨酸营养缺陷型的毒性降低所证明的。此外，该菌株的表型表征进一步揭示了从属谷胱甘肽氧化还原系统的鲁棒性。有趣的是，我们证明甲硫氨酸合酶是必不可少的A。烟曲霉的毒力，定义这种蛋白质氨基酸的生物合成途径作为一个潜在的抗真菌目标。总之，我们提供了新的见解的营养需求的A。在发病过程中，了解和对抗感染的先决条件。
Fungal infections are of major relevance due to the increased numbers of immunocompromised patients, frequently delayed diagnosis, and limited therapeutics. To date, the growth and nutritional requirements of fungi during infection, which are relevant for invasion of the host, are poorly understood. This is particularly true for invasive pulmonary aspergillosis, as so far, sources of (macro) elements that are exploited during infection have been identified to only a limited extent. Here, we have investigated sulfur (S) utilization by the human-pathogenic mold Aspergillus fumigatus during invasive growth. Our data reveal that inorganic S compounds or taurine is unlikely to serve as an S source during invasive pulmonary aspergillosis since a sulfate transporter mutant strain and a sulfite reductase mutant strain are fully virulent. In contrast, the S-containing amino acid cysteine is limiting for fungal growth, as proven by the reduced virulence of a cysteine auxotroph. Moreover, phenotypic characterization of this strain further revealed the robustness of the subordinate glutathione redox system. Interestingly, we demonstrate that methionine synthase is essential for A. fumigatus virulence, defining the biosynthetic route of this proteinogenic amino acid as a potential antifungal target. In conclusion, we provide novel insights into the nutritional requirements of A. fumigatus during pathogenesis, a prerequisite to understanding and fighting infection.