The pH of the host niche controls gene expression in and virulence of Candida albicans
The pH of the host niche controls gene expression in and virulence of Candida albicans
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DOI：
10.1128/iai.66.7.3317-3325.1998
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发表时间：
1998-07-01
影响因子：
3.1
通讯作者：
Fonzi, WA
中科院分区：
文献类型：
--
作者：
De Bernardis, F;Mühlschlegel, FA;Fonzi, WA
对于赋予机会性真菌病原体白色念珠菌致病性的生物学特性知之甚少。与细菌病原体一样，这种病原体的感染可能依赖于宿主生态位内的环境信号来调节毒力决定子的表达。为了确定白色念珠菌是否对宿主生态位的 pH 值做出反应，我们测试了两个 pH 调节基因 PHR1 和 PHR2 中带有突变的 bf 菌株的毒力。在体外，PHR1 在环境 pH 值为 5.5 或更高时表达，该基因的缺失会导致中性至碱性 pH 值下的生长和形态缺陷。相反，PHR2 在环境 pH 值低于 5.5 时表达，低于该 pH 值时无效突变体的生长和形态会受到影响。 PHR1无效突变体在全身感染的小鼠模型中是无毒的，但在大鼠中引起阴道感染的能力却丝毫不受影响。由于全身pH接近中性且阴道pH约为4.5，毒力表型与体外表型的pH依赖性平行，PHR2无效突变体的毒力表型则相反。该突变体在全身感染模型中具有毒力，但在阴道感染模型中无毒力。杂合突变体的致病潜力表现出部分降低，表明基因剂量效应。出乎意料的是，删除 PHR2 并没有阻止阴道组织中的菌丝发育，这表明它对于该宿主生态位中的菌丝发育不是必需的。结果表明，感染部位的 pH 值调节该生态位内生存所必需的基因的表达。这意味着环境调节基因的研究可能为理解白色念珠菌的病理学提供依据。
Little is known of the biological attributes conferring pathogenicity on the opportunistic fungal pathogen Candida albicans. Infection by this pathogen, as for bacterial pathogens, may rely upon environmental signals within the host niche to regulate the expression of virulence determinants. To determine if C. albicans responds to the pH of the host niche, we tested the virulence bf strains with mutations in either of two pH-regulated genes, PHR1 and PHR2. In vitro, PHR1 is expressed when the ambient pH is at 5.5 or higher and deletion of the gene results in growth and morphological defects at neutral to alkaline pHs. Conversely, PHR2 is expressed at an ambient pH below 5,5, and the growth and morphology of the null mutant is compromised below this pH. A PHR1 null mutant was avirulent in a mouse model of systemic infection but uncompromised in its ability to cause vaginal infection in rats. Since systemic pH is near neutrality and vaginal pH is around 4.5, the virulence phenotype paralleled the pH dependence of the in vitro phenotypes, The virulence phenotype of a PHR2 null mutant was the inverse. The mutant was virulent in a systemic-infection model but avirulent in a vaginal-infection model. Heterozygous mutants exhibited partial reductions in their pathogenic potential, suggesting a gene dosage effect. Unexpectedly, deletion of PHR2 did not prevent hyphal development in vaginal tissue, suggesting that it is not essential for hyphal development in this host niche. The results suggest that the pH of the infection site regulates the expression of genes essential to survival within that niche. This implies that the study of environmentally regulated genes may provide a rationale for understanding the pathobiology of C. albicans.