钙稳态系统在白念珠菌形态发生及压力应答中的功能研究
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摘要
白念珠菌是临床常见的条件性致病真菌之一。由于重症特护人群、免疫缺陷人群的增加及抗生素的滥用,白念珠菌感染,尤其是白念珠菌侵袭性感染备受人们关注。白念珠菌是一种典型的两型性真菌,具有菌丝发育、生物被膜形成等形态发生能力,这些能力与该真菌的形态发生调控网络及分泌途径具有密切联系。不仅如此,白念珠菌还具有极为精细的环境压力应答系统,用以感应抗真菌药物、氧化胁迫、营养匮乏等诸多环境压力,并对其作用应答,使自身得以存活与生长。白念珠菌的形态发生与压力应答能力均是白念珠菌在宿主体内进行有效定殖并造成感染所必需的,而这些能力又与白念珠菌钙稳态系统的功能紧密相关。
内质网与液泡是白念珠菌细胞两种极为重要的细胞器。前者是细胞分泌途径的核心,同时也是介导压力应答的主要细胞器。后者是白念珠菌细胞最主要的钙库,在调控细胞钙稳态方面扮演着重要角色。尽管白念珠菌钙稳态系统中的许多成员已为人们所知,但维持内质网功能所必需的钙泵尚未得到鉴定,且液泡钙通道Yvc1的功能仍属未知。此外,尽管人们已明确白念珠菌钙通道在形态发生及压力应答过程中发挥重要功能,但目前尚无有效抑制钙通道活性,进而指导临床实践的报道。本研究针对以上三个重要问题,对白念珠菌内质网钙泵进行鉴定及功能分析,并对液泡钙通道Yvc1的功能进行探索,同时研究钙通道阻断剂对白念珠菌形态发生及压力应答的影响,以期发现白念珠菌的新型毒力相关因子,并为临床治疗白念珠菌感染提供新的参考。本研究的主要结果如下：
(1)通过BLASTP分析,从白念珠菌基因组数据库中鉴定出一种内质网钙泵Spfl。序列比对分析发现,该蛋白属于V型P-ATPase家族成员。采用镍柱纯化技术,纯化得到Spfl蛋白,酶活分析发现该蛋白具有ATPase活性。通过对SPF1缺失菌株spf1△／△的研究发现,spf1△／△在正常生长条件下的生长速率明显降低,菌丝发育能力明显减弱,生物被膜形成、絮凝、粘附等能力显著下降,对抗真菌药物、低钙、高钙、氧化胁迫、碱性pH及膜损伤等诸多环境压力高度敏感,并且丧失了系统性感染小鼠的能力。上述结果表明,Spfl作为白念珠菌的内质网钙泵,在白念珠菌正常生长、形态发生及压力应答方面发挥着重要作用,是白念珠菌一种重要的毒力相关因子。
(2)采用fluo-3荧光探针法及原子吸收分光光度法,分析SPF1缺失对白念珠菌胞质钙及总钙含量的影响,发现其缺失导致压力条件下白念珠菌细胞钙稳态的严重紊乱,证明Spfl在维持细胞钙稳态方面扮演着重要角色。通过Western blotting及内切糖苷酶(EndoH)分析,发现SPF1缺失导致N-糖基化蛋白Cdc101及分泌型酸性磷酸酶(SAP)糖基化的缺陷,表明Spfl在维持内质网功能,尤其是其糖基化功能方面发挥作用。通过细胞壁压力敏感性测定,细胞壁重构及组分分析,发现SPFl缺失导致白念珠菌对细胞壁压力的敏感性增强,细胞壁重构能力降低以及细胞壁组成异常,揭示了Spfl在细胞壁完整性(CWI)维持方面的重要功能。β-半乳糖苷酶分析及RT-PCR结果表明,SPFl缺失影响白念珠菌诸多基因的表达,主要表现在钙应答基因CCH1,CWI基因PGA13、ECM331、 DFG5及氧化应答基因OYE32的表达显著上调,以及内质网功能必需基因SEC61,形态发生相关基因HWP1、ALS3及ECE1的表达显著下调。上述结果揭示了白念珠菌钙稳态系统、内质网压力应答系统与形态发生调控网络间存在紧密联系。
(3)液体培养及点板实验表明,yvc1Δ/Δ菌株表现为对低钙、高钙、碱性pH、氧化胁迫等诸多环境压力的敏感性增强；通过流式细胞技术,发现碱性刺激下yvc1Δ/Δ丧失了第二次钙波动的能力,而在高渗刺激下完全丧失钙波动的能力；在氧化胁迫条件下,yvc1Δ/Δ菌株的ROS水平显著偏高,抗氧化酶SOD与CAT的活性及氧化应答基因表达量均显著偏低。在形态发生方面,yvc1Δ/Δ菌株的菌丝发育、絮凝、侵染式生长、生物被膜形成等诸多形态发生能力均明显下降,形态发生相关基因的表达量显著下调。首次采用FM4-64及fluo-3对白念珠菌菌丝顶端液泡、顶体及胞质钙进行共染色,发现yvc1Δ/Δ菌丝顶端不存在液泡、顶体以及高钙梯度,表明Yvc1所介导的液泡钙释放在白念珠菌形态发生中发挥重要作用,而且这种作用与形态发生相关基因的表达以及极性生长有关。系统性感染及上皮细胞侵染实验表明,yvc1Δ/Δ菌株系统性感染小鼠的能力,以及侵染、损伤宿主上皮细胞及菌丝重新定向能力均显著下降。上述结果表明,Yvc1介导的液泡钙释放在白念珠菌压力应答及形态发生过程中发挥重要作用。
(4)采用酶标仪对fluo-3荧光信号进行动力学扫描,发现钙通道阻断剂维拉帕米(verapamil)能够明显抑制碱性刺激及药物刺激下白念珠菌的钙波动,而硝苯地平(nifedipine)同样明显抑制碱性刺激引起的钙波动,但对药物刺激下的钙内流不具有抑制作用。采用棋盘法(Chequerboard test)测定钙通道阻断剂与抗真菌药物对白念珠菌生长的协同抑制作用,发现verapamil与抗真菌药物氟康唑(fluconazole)、衣霉素(tunicamycin)具有协同作用,说明verapamil能够降低白念珠菌耐受抗真菌药物的能力,而nifedipine不具有该增强效应。在形态发生方面,verapamil能够明显抑制白念珠菌菌丝及生物被膜发育,并且能够增强抗真菌药物对生物被膜形成与维持的抑制作用。RT-PCR分析表明,verapamil的单独处理或与抗真菌药物联用能显著抑制ALS3基因的表达。上述结果揭示了verapamil对白念珠菌压力应答及形态发生的抑制作用,为临床白念珠菌感染的治疗提供了参考。
Candida albicans is one of the most important opportunistic fungal pathogens. Its infections, especially its invasive infections, were being paid attention due to the increase of ICU and immunocompromised individuals and the abuse of antibiotics. C. albicans is a typical diomorphic fungus, having the ability of morphogenesis, such as hyphal development and biofilm formation. This ability is closely associated with the morphogenesis regulation network and the secretory pathway. Moreover, This fungus evolved an elaborate stress response system to sense environmental stimuli, such as antifungal drugs, oxidative agents and nutrient depletion, and to respond to them for survival and growth. Both morphogenesis and stress response are essential for this fungus to effectively colonize and infect towards the host. Abundant evidence showed that the calcium homeostasis system plays an important role in these physiological processes.
Both the endoplasmic reticulum(ER) and the vacuole are of significance in C. albicans cells. The ER is the centre of the secretory pathway, and is the main organelle mediating stress response, while the vacuole is the main calcium store which is indispensible for calcium homeostasis. Although many members of the calcium homeostasis system have been elucidated, the ER pump and the vacuolar channel has not been well characterized. Furthermore, although the role of calcium channels in morphogenesis and stress response has been confirmed, there has not yet been any strategy to inhibit these channels. Therefore, in this study, we identified and characterized both the ER pump and the vacuolar channel Yvcl, and investigated the effect of calcium channel blockers on morphogenesis and stress response in C. albicans. The main results were demonstrated as follows.
(1) By BLASTP analysis, we identified an ER pump and named it Spfl. This protein belongs to the V-type P-ATPase family. By nickel affinity chromatography and ATPase assays, Spfl is confirmed to have the ability of ATPases. The SPF1-disrupted strain spf1Δ/Δ showed decreased growth rate under normal growth conditions, reduced ability of hyphal development under hyphal-inducing conditions, and a defect in biofilm formation, flocculation and adhesion. Moreover, the mutant displayed hypersensitivity to such environmental stresses as antifungal drugs, low or high calcium levels, oxidative agents, alkaline pH and membrane damage. Systemic infection model further demonstrated that the mutant was severely attenuated in virulence. These results revealed that Spfl plays an important role in cell growth, morphogenesis and stress response in C. albicans. Therefore, it is an key virulence factor of this pathogen.
(2) The effect of SPF1disruption on cytoplasmic and total calcium content was determined by fluo-3staining and atom absorption spectrophotometry. It was confirmed that Spfl functions as an key member of the calcium homestasis. Westerin blotting and EndoH analysis revealed that the disruption of SPF1led to the defect in N-glycosylation of Cdc101and secreted acid phosphatase (SAP). Moreover, Spfl is essential for cell wall integrity (CWI). The disruption caused hypersensitivity to cell wall stresses, decreased cell wall reconstruction, and abnormal cell wall compositions. Due to the important role of this protein, disruption of SPF1affected the expression of many genes, resulting in up-regulation of the calcium response gene CCH1, the CWI genes PGA13, ECM331, DFG5and the oxidative stress response gene OYE32, and down-regulation of the ER essential gene SEC61and the morphogenesis-related genes HWP1, ALS3and ECE1. These results revealed the close link between the calcium homeostasis system, the ER stress response system and the morphogenesis regulation network.
(3) The vacuolar calcium channel Yvcl is also necessary for stress response, morphogenesis and pathogenicity of C. albicans. In terms of stress response, yvc1Δ/Δ displayed increased sensitivity to low or high calcium levels, alkaline pH and oxidative agents, defects in calcium fluctuation under alkaline or hypertonic stimulus, decreased levels of the antioxidases and down-regulation of oxidative stress response genes. As for, morphogenesis, the mutant had defects in hyphal development, flocculation, invasive growth and biofilm formation, tip-localization of the vacuole and the Spitzenkorper, and calcium accumulation at the tip, and displayed decreased expression of morphogenesis-related genes, indicating an essential role of Yvcl in morphogenesis of C. albicans, which is associated with the expression of morphogenesis-related genes and polarized growth. Moreover, the mutant showed decreased virulence during systemic infection and reduced ability of invading, damaging host epithelial cells and re-orienting to the cells, suggesting that Yvcl is another important virulence factor in C. albicans.
(4) The calcium channel blockers verapamil and nifedipine could significantly inhibit calcium fluctuation of C. albicans cells under alkaline stimulus. However, while verapamil could also inhibit calcium influx under the stress caused by antifungal drugs, nifedipine showed no inhibitory effect under this stress. When used in combination with the antifungal drugs, fluconazole and tunicamycin, verapamil could enhance the inhibitory effect of antifungal drugs against this fungus, whereas nifedipine could not. Furthermore, verapamil inhibited hyphal development, biofilm formation and biofilm maintenance, and enhanced the inhibitory effect of antifungal drugs against biofilms. RT-PCR assays further revealed that verapamil alone or in combination with antifungal drugs led to decreased expression of the morphogenesis-related gene, ALS3, suggesting that the effect of verapamil on morphogenesis is associated with down-regulation of morphogenesis-related genes in C. albicans. These results revealed the inhibitory effect of verapamil on drug tolerance and morphogenesis, providing a novel strategy against C. albicans infections.
内质网与液泡是白念珠菌细胞两种极为重要的细胞器。前者是细胞分泌途径的核心,同时也是介导压力应答的主要细胞器。后者是白念珠菌细胞最主要的钙库,在调控细胞钙稳态方面扮演着重要角色。尽管白念珠菌钙稳态系统中的许多成员已为人们所知,但维持内质网功能所必需的钙泵尚未得到鉴定,且液泡钙通道Yvc1的功能仍属未知。此外,尽管人们已明确白念珠菌钙通道在形态发生及压力应答过程中发挥重要功能,但目前尚无有效抑制钙通道活性,进而指导临床实践的报道。本研究针对以上三个重要问题,对白念珠菌内质网钙泵进行鉴定及功能分析,并对液泡钙通道Yvc1的功能进行探索,同时研究钙通道阻断剂对白念珠菌形态发生及压力应答的影响,以期发现白念珠菌的新型毒力相关因子,并为临床治疗白念珠菌感染提供新的参考。本研究的主要结果如下：
(1)通过BLASTP分析,从白念珠菌基因组数据库中鉴定出一种内质网钙泵Spfl。序列比对分析发现,该蛋白属于V型P-ATPase家族成员。采用镍柱纯化技术,纯化得到Spfl蛋白,酶活分析发现该蛋白具有ATPase活性。通过对SPF1缺失菌株spf1△／△的研究发现,spf1△／△在正常生长条件下的生长速率明显降低,菌丝发育能力明显减弱,生物被膜形成、絮凝、粘附等能力显著下降,对抗真菌药物、低钙、高钙、氧化胁迫、碱性pH及膜损伤等诸多环境压力高度敏感,并且丧失了系统性感染小鼠的能力。上述结果表明,Spfl作为白念珠菌的内质网钙泵,在白念珠菌正常生长、形态发生及压力应答方面发挥着重要作用,是白念珠菌一种重要的毒力相关因子。
(2)采用fluo-3荧光探针法及原子吸收分光光度法,分析SPF1缺失对白念珠菌胞质钙及总钙含量的影响,发现其缺失导致压力条件下白念珠菌细胞钙稳态的严重紊乱,证明Spfl在维持细胞钙稳态方面扮演着重要角色。通过Western blotting及内切糖苷酶(EndoH)分析,发现SPF1缺失导致N-糖基化蛋白Cdc101及分泌型酸性磷酸酶(SAP)糖基化的缺陷,表明Spfl在维持内质网功能,尤其是其糖基化功能方面发挥作用。通过细胞壁压力敏感性测定,细胞壁重构及组分分析,发现SPFl缺失导致白念珠菌对细胞壁压力的敏感性增强,细胞壁重构能力降低以及细胞壁组成异常,揭示了Spfl在细胞壁完整性(CWI)维持方面的重要功能。β-半乳糖苷酶分析及RT-PCR结果表明,SPFl缺失影响白念珠菌诸多基因的表达,主要表现在钙应答基因CCH1,CWI基因PGA13、ECM331、 DFG5及氧化应答基因OYE32的表达显著上调,以及内质网功能必需基因SEC61,形态发生相关基因HWP1、ALS3及ECE1的表达显著下调。上述结果揭示了白念珠菌钙稳态系统、内质网压力应答系统与形态发生调控网络间存在紧密联系。
(3)液体培养及点板实验表明,yvc1Δ/Δ菌株表现为对低钙、高钙、碱性pH、氧化胁迫等诸多环境压力的敏感性增强；通过流式细胞技术,发现碱性刺激下yvc1Δ/Δ丧失了第二次钙波动的能力,而在高渗刺激下完全丧失钙波动的能力；在氧化胁迫条件下,yvc1Δ/Δ菌株的ROS水平显著偏高,抗氧化酶SOD与CAT的活性及氧化应答基因表达量均显著偏低。在形态发生方面,yvc1Δ/Δ菌株的菌丝发育、絮凝、侵染式生长、生物被膜形成等诸多形态发生能力均明显下降,形态发生相关基因的表达量显著下调。首次采用FM4-64及fluo-3对白念珠菌菌丝顶端液泡、顶体及胞质钙进行共染色,发现yvc1Δ/Δ菌丝顶端不存在液泡、顶体以及高钙梯度,表明Yvc1所介导的液泡钙释放在白念珠菌形态发生中发挥重要作用,而且这种作用与形态发生相关基因的表达以及极性生长有关。系统性感染及上皮细胞侵染实验表明,yvc1Δ/Δ菌株系统性感染小鼠的能力,以及侵染、损伤宿主上皮细胞及菌丝重新定向能力均显著下降。上述结果表明,Yvc1介导的液泡钙释放在白念珠菌压力应答及形态发生过程中发挥重要作用。
(4)采用酶标仪对fluo-3荧光信号进行动力学扫描,发现钙通道阻断剂维拉帕米(verapamil)能够明显抑制碱性刺激及药物刺激下白念珠菌的钙波动,而硝苯地平(nifedipine)同样明显抑制碱性刺激引起的钙波动,但对药物刺激下的钙内流不具有抑制作用。采用棋盘法(Chequerboard test)测定钙通道阻断剂与抗真菌药物对白念珠菌生长的协同抑制作用,发现verapamil与抗真菌药物氟康唑(fluconazole)、衣霉素(tunicamycin)具有协同作用,说明verapamil能够降低白念珠菌耐受抗真菌药物的能力,而nifedipine不具有该增强效应。在形态发生方面,verapamil能够明显抑制白念珠菌菌丝及生物被膜发育,并且能够增强抗真菌药物对生物被膜形成与维持的抑制作用。RT-PCR分析表明,verapamil的单独处理或与抗真菌药物联用能显著抑制ALS3基因的表达。上述结果揭示了verapamil对白念珠菌压力应答及形态发生的抑制作用,为临床白念珠菌感染的治疗提供了参考。
Candida albicans is one of the most important opportunistic fungal pathogens. Its infections, especially its invasive infections, were being paid attention due to the increase of ICU and immunocompromised individuals and the abuse of antibiotics. C. albicans is a typical diomorphic fungus, having the ability of morphogenesis, such as hyphal development and biofilm formation. This ability is closely associated with the morphogenesis regulation network and the secretory pathway. Moreover, This fungus evolved an elaborate stress response system to sense environmental stimuli, such as antifungal drugs, oxidative agents and nutrient depletion, and to respond to them for survival and growth. Both morphogenesis and stress response are essential for this fungus to effectively colonize and infect towards the host. Abundant evidence showed that the calcium homeostasis system plays an important role in these physiological processes.
Both the endoplasmic reticulum(ER) and the vacuole are of significance in C. albicans cells. The ER is the centre of the secretory pathway, and is the main organelle mediating stress response, while the vacuole is the main calcium store which is indispensible for calcium homeostasis. Although many members of the calcium homeostasis system have been elucidated, the ER pump and the vacuolar channel has not been well characterized. Furthermore, although the role of calcium channels in morphogenesis and stress response has been confirmed, there has not yet been any strategy to inhibit these channels. Therefore, in this study, we identified and characterized both the ER pump and the vacuolar channel Yvcl, and investigated the effect of calcium channel blockers on morphogenesis and stress response in C. albicans. The main results were demonstrated as follows.
(1) By BLASTP analysis, we identified an ER pump and named it Spfl. This protein belongs to the V-type P-ATPase family. By nickel affinity chromatography and ATPase assays, Spfl is confirmed to have the ability of ATPases. The SPF1-disrupted strain spf1Δ/Δ showed decreased growth rate under normal growth conditions, reduced ability of hyphal development under hyphal-inducing conditions, and a defect in biofilm formation, flocculation and adhesion. Moreover, the mutant displayed hypersensitivity to such environmental stresses as antifungal drugs, low or high calcium levels, oxidative agents, alkaline pH and membrane damage. Systemic infection model further demonstrated that the mutant was severely attenuated in virulence. These results revealed that Spfl plays an important role in cell growth, morphogenesis and stress response in C. albicans. Therefore, it is an key virulence factor of this pathogen.
(2) The effect of SPF1disruption on cytoplasmic and total calcium content was determined by fluo-3staining and atom absorption spectrophotometry. It was confirmed that Spfl functions as an key member of the calcium homestasis. Westerin blotting and EndoH analysis revealed that the disruption of SPF1led to the defect in N-glycosylation of Cdc101and secreted acid phosphatase (SAP). Moreover, Spfl is essential for cell wall integrity (CWI). The disruption caused hypersensitivity to cell wall stresses, decreased cell wall reconstruction, and abnormal cell wall compositions. Due to the important role of this protein, disruption of SPF1affected the expression of many genes, resulting in up-regulation of the calcium response gene CCH1, the CWI genes PGA13, ECM331, DFG5and the oxidative stress response gene OYE32, and down-regulation of the ER essential gene SEC61and the morphogenesis-related genes HWP1, ALS3and ECE1. These results revealed the close link between the calcium homeostasis system, the ER stress response system and the morphogenesis regulation network.
(3) The vacuolar calcium channel Yvcl is also necessary for stress response, morphogenesis and pathogenicity of C. albicans. In terms of stress response, yvc1Δ/Δ displayed increased sensitivity to low or high calcium levels, alkaline pH and oxidative agents, defects in calcium fluctuation under alkaline or hypertonic stimulus, decreased levels of the antioxidases and down-regulation of oxidative stress response genes. As for, morphogenesis, the mutant had defects in hyphal development, flocculation, invasive growth and biofilm formation, tip-localization of the vacuole and the Spitzenkorper, and calcium accumulation at the tip, and displayed decreased expression of morphogenesis-related genes, indicating an essential role of Yvcl in morphogenesis of C. albicans, which is associated with the expression of morphogenesis-related genes and polarized growth. Moreover, the mutant showed decreased virulence during systemic infection and reduced ability of invading, damaging host epithelial cells and re-orienting to the cells, suggesting that Yvcl is another important virulence factor in C. albicans.
(4) The calcium channel blockers verapamil and nifedipine could significantly inhibit calcium fluctuation of C. albicans cells under alkaline stimulus. However, while verapamil could also inhibit calcium influx under the stress caused by antifungal drugs, nifedipine showed no inhibitory effect under this stress. When used in combination with the antifungal drugs, fluconazole and tunicamycin, verapamil could enhance the inhibitory effect of antifungal drugs against this fungus, whereas nifedipine could not. Furthermore, verapamil inhibited hyphal development, biofilm formation and biofilm maintenance, and enhanced the inhibitory effect of antifungal drugs against biofilms. RT-PCR assays further revealed that verapamil alone or in combination with antifungal drugs led to decreased expression of the morphogenesis-related gene, ALS3, suggesting that the effect of verapamil on morphogenesis is associated with down-regulation of morphogenesis-related genes in C. albicans. These results revealed the inhibitory effect of verapamil on drug tolerance and morphogenesis, providing a novel strategy against C. albicans infections.
引文
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