荚膜独立吞噬抑制机制在新型隐球菌感染哺乳动物中的主要作用。
A major role for capsule-independent phagocytosis-inhibitory mechanisms in mammalian infection by Cryptococcus neoformans.
机构信息
Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16(th) Street, San Francisco, CA 94158-2200, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16(th) Street, San Francisco, CA 94158-2200, USA.
出版信息
Cell Host Microbe. 2011 Mar 17;9(3):243-251. doi: 10.1016/j.chom.2011.02.003.
The antiphagocytic polysaccharide capsule of the human fungal pathogen Cryptococcus neoformans is a major virulence attribute. However, previous studies of the pleiotropic virulence determinant Gat201, a GATA family transcription factor, suggested that capsule-independent antiphagocytic mechanisms exist. We have determined that Gat201 controls the mRNA levels of ∼1100 genes (16% of the genome) and binds the upstream regions of ∼130 genes. Seven Gat201-bound genes encode for putative and known transcription factors--including two previously implicated in virulence--suggesting an extensive regulatory network. Systematic analysis pinpointed two critical Gat201-bound genes, GAT204 (a transcription factor) and BLP1, which account for much of the capsule-independent antiphagocytic function of Gat201. A strong correlation was observed between the quantitative effects of single and double mutants on phagocytosis in vitro and on host colonization in vivo. This genetic dissection provides evidence that capsule-independent antiphagocytic mechanisms are pivotal for successful mammalian infection by C. neoformans.
人类真菌病原体新型隐球菌的抗吞噬多糖荚膜是主要的毒力属性。然而，先前对多效性毒力决定因子 Gat201（一个 GATA 家族转录因子）的研究表明，存在不依赖荚膜的抗吞噬机制。我们已经确定 Gat201 控制着约 1100 个基因（基因组的 16%）的 mRNA 水平，并结合了约 130 个基因的上游区域。Gat201 结合的七个基因编码假定和已知的转录因子——包括两个先前与毒力有关的转录因子——表明存在广泛的调控网络。系统分析确定了两个关键的 Gat201 结合基因 Gat204（一个转录因子）和 BLP1，它们解释了 Gat201 不依赖荚膜的大部分抗吞噬功能。在体外吞噬作用和体内定植方面，单突变体和双突变体的定量效应之间存在很强的相关性。这种遗传剖析提供了证据，表明不依赖荚膜的抗吞噬机制对于新型隐球菌成功感染哺乳动物至关重要。
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