A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus.
A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus.
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DOI：
10.1080/21505594.2018.1526528
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发表时间：
2018
期刊：
影响因子：
5.2
通讯作者：
Rementeria A
中科院分区：
文献类型：
--
作者：
Guruceaga X;Ezpeleta G;Mayayo E;Sueiro-Olivares M;Abad-Diaz-De-Cerio A;Aguirre Urízar JM;Liu HG;Wiemann P;Bok JW;Filler SG;Keller NP;Hernando FL;Ramirez-Garcia A;Rementeria A
病原真菌烟曲霉（Aspergillus fumigatus）的毒力机制是多因素的，依赖于宿主的免疫状态，但对真菌在肺部侵袭过程中形成的机制知之甚少。在这项研究中，微阵列技术与感染肺部的组织病理学评估相结合，从而可以描述真菌的入侵策略。为了实现这一目标，在感染后4天内对小鼠进行鼻内感染，每天从感染的肺部提取真菌样本。病理研究显示肺部真菌严重恶化，暴露后第三天到达血管并引起组织坏死。在这个过程中，1%的真菌基因组遵循差异表达模式。值得注意的是，富马青霉素/伪黄素生物合成基因簇的大部分基因都上调了，编码脂肪酶、蛋白酶（DppIV、DppV、Asp 1或Asp 5）和几丁质酶（chiB1）等裂解酶的基因以及三个与脓黑素生物合成过程相关的基因也上调了。此外，我们证明了富马青霉素是在体外肺细胞系感染模型中产生的，富马青霉素合成的缺失减少了上皮细胞的损伤。这些结果表明，富马青霉素有助于侵袭性曲霉病期间的组织损伤。因此，烟曲霉可能是通过真菌毒素富马青霉素的产生，以及允许真菌生长、血管入侵和破坏肺实质结构的裂解酶的分泌，在肺中传播的。
Virulence mechanisms of the pathogenic fungus Aspergillus fumigatus are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an in vitro pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that A. fumigatus progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure.
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影响因子：
5.2
作者：
Escobar N;Ordonez SR;Wösten HA;Haas PJ;de Cock H;Haagsman HP
通讯作者：
Haagsman HP
影响因子：
20.3
作者：
Bezerra, LML;Filler, SG
通讯作者：
Filler, SG
影响因子：
3.7
作者：
Dhingra S;Lind AL;Lin HC;Tang Y;Rokas A;Calvo AM
通讯作者：
Calvo AM
影响因子：
2.9
作者：
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通讯作者：
Hope, William W.
影响因子：
3.1
作者：
Gravelat, Fabrice N.;Doedt, Thomas;Sheppard, Donald C.
通讯作者：
Sheppard, Donald C.