Host cell invasion and virulence mediated by Candida albicans Ssa1.
Host cell invasion and virulence mediated by Candida albicans Ssa1.
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DOI：
10.1371/journal.ppat.1001181
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发表时间：
2010-11-11
期刊：
影响因子：
6.7
通讯作者：
Filler SG
中科院分区：
文献类型：
--
作者：
Sun JN;Solis NV;Phan QT;Bajwa JS;Kashleva H;Thompson A;Liu Y;Dongari-Bagtzoglou A;Edgerton M;Filler SG
白色念珠菌Ssa1和Ssa2是热休克蛋白HSP70家族的成员，在细胞表面表达，作为抗微生物肽（如组抑素）的受体。我们研究了Ssa1和Ssa2在介导致病性宿主细胞相互作用和毒力中的作用。白色念珠菌ssa1Δ/Δ突变体在播散性和口咽念珠菌病小鼠模型中具有减弱的毒力，而ssa2Δ/Δ突变体则没有。体外研究表明，ssa1Δ/Δ突变体对内皮细胞和口腔上皮细胞系的损伤明显较小。此外，ssa1Δ/Δ突变体与内皮细胞N-cadherin和上皮细胞E-cadherin的结合存在缺陷，这两种受体介导白色假丝酵母菌的宿主细胞内噬。结果，该突变体诱导内皮细胞和口腔上皮细胞自身内吞作用的能力受损。经重组Ssa1包被的乳胶珠被内皮细胞和口腔上皮细胞大量内吞，表明Ssa1足以诱导宿主细胞内吞作用。这些结果表明，Ssa1是一种与宿主细胞钙粘蛋白结合，诱导宿主细胞内吞作用的新型入侵蛋白，是白色念珠菌对宿主细胞造成最大损伤和诱发弥散性口咽疾病的关键。白色念珠菌可以在口腔内增殖，引起口咽念珠菌病。在其他患者中，它可以进入血液并扩散到全身，导致血源性播散性念珠菌病。真菌侵入宿主细胞是这两种感染的关键特征。白色念珠菌侵入口咽部上皮细胞和血管内皮细胞的一种机制是通过诱导自身摄取。这种摄取部分是由白色念珠菌侵入性蛋白al3与宿主细胞蛋白（包括N-和e -钙粘蛋白）结合引起的。在这里，我们发现白色念珠菌Ssa1是70 kDa热休克蛋白家族的成员，在白色念珠菌表面表达，并作为入侵蛋白发挥作用。在体外实验中，一个ssa1Δ/Δ零突变体诱导其自身被上皮细胞和内皮细胞摄取的能力降低，以及该突变体在口咽念珠菌病和播散性念珠菌病小鼠模型中的毒力显著减弱，说明了Ssa1在宿主细胞侵袭中的关键作用。因此，Ssa1是第二个确定的白色念珠菌入侵。
Candida albicans Ssa1 and Ssa2 are members of the HSP70 family of heat shock proteins that are expressed on the cell surface and function as receptors for antimicrobial peptides such as histatins. We investigated the role of Ssa1 and Ssa2 in mediating pathogenic host cell interactions and virulence. A C. albicans ssa1Δ/Δ mutant had attenuated virulence in murine models of disseminated and oropharyngeal candidiasis, whereas an ssa2Δ/Δ mutant did not. In vitro studies revealed that the ssa1Δ/Δ mutant caused markedly less damage to endothelial cells and oral epithelial cell lines. Also, the ssa1Δ/Δ mutant had defective binding to endothelial cell N-cadherin and epithelial cell E-cadherin, receptors that mediate host cell endocytosis of C. albicans. As a result, this mutant had impaired capacity to induce its own endocytosis by endothelial cells and oral epithelial cells. Latex beads coated with recombinant Ssa1 were avidly endocytosed by both endothelial cells and oral epithelial cells, demonstrating that Ssa1 is sufficient to induce host cell endocytosis. These results indicate that Ssa1 is a novel invasin that binds to host cell cadherins, induces host cell endocytosis, and is critical for C. albicans to cause maximal damage to host cells and induce disseminated and oropharyngeal disease. The fungus Candida albicans can proliferate in the mouth, causing oropharyngeal candidiasis. In other patients, it can enter the bloodstream and spread throughout the body, resulting in hematogenously disseminated candidiasis. Fungal invasion of host cells is a key feature of both types of infection. One mechanism by which C. albicans invades both the epithelial cell lining of the oropharynx and the endothelial cell lining of the blood vessels is by inducing its own uptake. This uptake is induced in part by the binding of the C. albicans invasin Als3 to host cell proteins, which include N- and E-cadherin. Here we show that C. albicans Ssa1, a member of the 70 kDa heat shock protein family, is expressed on the surface of C. albicans where it functions as an invasin. The key role of Ssa1 in host cell invasion is illustrated by the reduced capacity of an ssa1Δ/Δ null mutant to induce its own uptake by epithelial and endothelial cells in vitro, and by the significantly attenuated virulence of this mutant in mouse models of oropharyngeal candidiasis and disseminated candidiasis. Thus, Ssa1 is the second identified invasin of C. albicans.
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影响因子：
15.9
作者：
JAFFE, EA;NACHMAN, RL;MINICK, CR
通讯作者：
MINICK, CR
影响因子：
6.4
作者：
De Bernardis, F;Arancia, S;Cassone, A
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影响因子：
4.9
作者：
Kamai, Y;Kubota, M;Filler, SG
通讯作者：
Filler, SG
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2.9
作者：
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通讯作者：
Kashleva, H
影响因子：
3.1
作者：
Folgueira, Cristina;Carrion, Javier;Requena, Jose M.
通讯作者：
Requena, Jose M.