Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals hyphal β-glucan from the immune system.
Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals hyphal β-glucan from the immune system.
复制标题
DOI：
10.1371/journal.ppat.1003575
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Sheppard DC
中科院分区：
文献类型：
--
作者：
Gravelat FN;Beauvais A;Liu H;Lee MJ;Snarr BD;Chen D;Xu W;Kravtsov I;Hoareau CM;Vanier G;Urb M;Campoli P;Al Abdallah Q;Lehoux M;Chabot JC;Ouimet MC;Baptista SD;Fritz JH;Nierman WC;Latgé JP;Mitchell AP;Filler SG;Fontaine T;Sheppard DC
烟曲霉菌是人类侵袭性霉菌病最常见的原因。这种霉菌附着在宿主细胞和大分子上的机制仍然不清楚。利用具有不同粘附性的突变体和比较转录学，我们发现编码真菌差向异构酶的基因uge3通过介导半乳糖氨基半乳糖的合成来实现粘附性。半乳糖氨基半乳糖是烟曲霉菌的主要粘附素，介导与塑料、纤维连接蛋白和上皮细胞的黏附。此外，半乳糖氨基半乳糖在体外和体内抑制宿主炎症反应，部分是通过掩盖细胞壁β-葡聚糖不被Dectin-1识别而实现的。最后，在两种侵袭性曲霉病小鼠模型中，半乳糖氨基半乳糖是完全毒力所必需的。总而言之，这些数据确立了半乳糖氨基半乳糖在侵袭性曲霉病发病机制中的作用，它是一个关键的双功能毒力因子。侵袭性曲霉病是人类最常见的霉菌感染，主要影响免疫功能低下的患者。霉菌烟曲霉菌附着在宿主组织上并导致疾病的机制还知之甚少。在这份报告中，我们比较了具有不同粘附性的曲霉突变株，以确定与宿主细胞粘附性有关的真菌因素。这种方法确定了一种与细胞壁相关的多糖，半乳糖氨基半乳糖，它是附着在各种底物上所必需的。半乳糖氨基半乳糖还被观察到通过隐藏β-葡聚糖来抑制炎症，Gluan-葡聚糖是曲霉菌丝中的关键模式相关微生物模式分子，不被天然免疫系统识别。在侵袭性曲霉病小鼠模型中，缺乏半乳糖氨基半乳糖的突变株的毒力较低。这些数据证实了半乳糖氨基半乳糖在侵袭性曲霉病发病机制中的双功能作用，并提示它可能成为抗真菌治疗的有用靶点。
Aspergillus fumigatus is the most common cause of invasive mold disease in humans. The mechanisms underlying the adherence of this mold to host cells and macromolecules have remained elusive. Using mutants with different adhesive properties and comparative transcriptomics, we discovered that the gene uge3, encoding a fungal epimerase, is required for adherence through mediating the synthesis of galactosaminogalactan. Galactosaminogalactan functions as the dominant adhesin of A. fumigatus and mediates adherence to plastic, fibronectin, and epithelial cells. In addition, galactosaminogalactan suppresses host inflammatory responses in vitro and in vivo, in part through masking cell wall β-glucans from recognition by dectin-1. Finally, galactosaminogalactan is essential for full virulence in two murine models of invasive aspergillosis. Collectively these data establish a role for galactosaminogalactan as a pivotal bifunctional virulence factor in the pathogenesis of invasive aspergillosis. Invasive aspergillosis is the most common mold infection in humans, predominately affecting immunocompromised patients. The mechanisms by which the mold Aspergillus fumigatus adheres to host tissues and causes disease are poorly understood. In this report, we compared mutants of Aspergillus with different adhesive properties to identify fungal factors involved in adherence to host cells. This approach identified a cell wall associated polysaccharide, galactosaminogalactan, which is required for adherence to a wide variety of substrates. Galactosaminogalactan was also observed to suppress inflammation by concealing β-glucans, key pattern associated microbial pattern molecules in Aspergillus hyphae, from recognition by the innate immune system. Mutants that were deficient in galactosaminogalactan were less virulent in mouse models of invasive aspergillosis. These data identify a bifunctional role for galactosaminogalactan in the pathogenesis of invasive aspergillosis, and suggest that it may serve as a useful target for antifungal therapy.
登录
查看更多内容
DOI：
10.1086/591969
发表时间：
2008-10-15
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Garcia-Vidal C;Upton A;Kirby KA;Marr KA
通讯作者：
Marr KA
影响因子：
4.9
作者：
Bowman, JC;Abruzzo, GK;Douglas, CM
通讯作者：
Douglas, CM
影响因子：
20.3
作者：
Bezerra, LML;Filler, SG
通讯作者：
Filler, SG
影响因子：
6.9
作者：
BRIAN, PW;NORRIS, GLF;LOWE, D
通讯作者：
LOWE, D
影响因子：
3.1
作者：
Gravelat, Fabrice N.;Doedt, Thomas;Sheppard, Donald C.
通讯作者：
Sheppard, Donald C.