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Abstract：
Candida albicans causes millions of mucosal infections in humans annually. Hyphal overgrowth on mucosal surfaces is frequently associated with tissue damage caused by candidalysin, a secreted peptide toxin that destabilizes the plasma membrane of host cells thereby promoting disease and immunopathology. Candidalysin was first identified in C. albicans strain SC5314, but recent investigations have revealed candidalysin \"variants\" of differing amino acid sequence in isolates of C. albicans, and the related species C. dubliniensis, and C tropicalis, suggesting that sequence variation among candidalysins may be widespread in natural populations of these Candida species. Here, we analyzed ECE1 gene sequences from 182 C. albicans isolates, 10 C. dubliniensis isolates, and 78 C. tropicalis isolates and identified 10, 3, and 2 candidalysin variants in these species, respectively. Application of candidalysin variants to epithelial cells revealed differences in the ability to cause cellular damage, changes in metabolic activity, calcium influx, MAPK signalling, and cytokine secretion, while biophysical analyses indicated that variants exhibited differences in their ability to interact with and permeabilize a membrane. This study identifies candidalysin variants with differences in biological activity that are present in medically relevant Candida species.
OBJECTIVE: Fungal infections are a significant burden to health. Candidalysin is a toxin produced by Candida albicans that damages host tissues, facilitating infection. Previously, we demonstrated that candidalysins exist in the related species C. dubliniensis and C. tropicalis, thereby identifying these molecules as a toxin family. Recent genomic analyses have highlighted the presence of a small number of candidalysin \"variant\" toxins, which have different amino acid sequences to those originally identified. Here, we screened genome sequences of isolates of C. albicans, C. dubliniensis, and C. tropicalis and identified candidalysin variants in all three species. When applied to epithelial cells, candidalysin variants differed in their ability to cause damage, activate intracellular signaling pathways, and induce innate immune responses, while biophysical analysis revealed differences in the ability of candidalysin variants to interact with lipid bilayers. These findings suggest that intraspecies variation in candidalysin amino acid sequence may influence fungal pathogenicity.
OBJECTIVE: Fungal infections are a significant burden to health. Candidalysin is a toxin produced by Candida albicans that damages host tissues, facilitating infection. Previously, we demonstrated that candidalysins exist in the related species C. dubliniensis and C. tropicalis, thereby identifying these molecules as a toxin family. Recent genomic analyses have highlighted the presence of a small number of candidalysin \"variant\" toxins, which have different amino acid sequences to those originally identified. Here, we screened genome sequences of isolates of C. albicans, C. dubliniensis, and C. tropicalis and identified candidalysin variants in all three species. When applied to epithelial cells, candidalysin variants differed in their ability to cause damage, activate intracellular signaling pathways, and induce innate immune responses, while biophysical analysis revealed differences in the ability of candidalysin variants to interact with lipid bilayers. These findings suggest that intraspecies variation in candidalysin amino acid sequence may influence fungal pathogenicity.
摘要：
白色念珠菌每年在人类中引起数百万的粘膜感染。粘膜表面的菌丝过度生长通常与念珠菌素引起的组织损伤有关。一种分泌的肽毒素，使宿主细胞的质膜不稳定，从而促进疾病和免疫病理学。念珠菌素最初是在白色念珠菌菌株SC5314中鉴定的，但最近的调查显示，念珠菌素“变体”在白色念珠菌的分离物中具有不同的氨基酸序列，和相关物种C.dubliniensis，和热带C，表明念珠菌之间的序列变异可能在这些念珠菌物种的自然种群中普遍存在。这里,我们分析了182株白色念珠菌分离株的ECE1基因序列，10杜布林杆菌分离株，和78个热带念珠菌分离，并在这些物种中鉴定出10、3和2个念珠菌变种，分别。将念珠菌素变体应用于上皮细胞揭示了引起细胞损伤的能力差异，代谢活动的变化，钙内流，MAPK信号,和细胞因子分泌，而生物物理分析表明，变体在与膜相互作用和透化膜的能力上表现出差异。这项研究确定了在医学相关的念珠菌物种中存在生物活性差异的念珠菌素变体。
目的：真菌感染是健康的重大负担。念珠菌毒素是白色念珠菌产生的毒素，会损害宿主组织，促进感染。以前,我们证明了念珠菌存在于相关物种都柏林和热带念珠菌中，从而将这些分子鉴定为毒素家族。最近的基因组分析强调了少量念珠菌毒素的存在，与最初鉴定的氨基酸序列不同。这里,我们筛选了白色念珠菌分离株的基因组序列，都柏林人，和热带念珠菌，并在所有三个物种中鉴定了念珠菌素变体。当应用于上皮细胞时，念珠菌素变体在造成损害的能力上有所不同，激活细胞内信号通路，并诱导先天免疫反应，而生物物理分析显示，念珠菌素变体与脂质双层相互作用的能力存在差异。这些发现表明念珠菌氨基酸序列的种内变异可能会影响真菌的致病性。
目的：真菌感染是健康的重大负担。念珠菌毒素是白色念珠菌产生的毒素，会损害宿主组织，促进感染。以前,我们证明了念珠菌存在于相关物种都柏林和热带念珠菌中，从而将这些分子鉴定为毒素家族。最近的基因组分析强调了少量念珠菌毒素的存在，与最初鉴定的氨基酸序列不同。这里,我们筛选了白色念珠菌分离株的基因组序列，都柏林人，和热带念珠菌，并在所有三个物种中鉴定了念珠菌素变体。当应用于上皮细胞时，念珠菌素变体在造成损害的能力上有所不同，激活细胞内信号通路，并诱导先天免疫反应，而生物物理分析显示，念珠菌素变体与脂质双层相互作用的能力存在差异。这些发现表明念珠菌氨基酸序列的种内变异可能会影响真菌的致病性。
