Sem XiaoHui, Le Giang T T, Tan Alrina S M, Tso Gloria, Yurieva Marina, Liao Webber W P, Lum Josephine, Srinivasan Kandhadayar G, Poidinger Michael, Zolezzi Francesca, Pavelka Norman
Singapore Immunology Network, Agency for Science, Technology and Research Singapore, Singapore.
Front Cell Infect Microbiol. 2016 Dec 22;6:186. doi: 10.3389/fcimb.2016.00186. eCollection 2016.
is responsible for ~400,000 systemic fungal infections annually, with an associated mortality rate of 46-75%. The human gastrointestinal (GI) tract represents the largest natural reservoir of species and is a major source of systemic fungal infections. However, the factors that control GI colonization by species are not completely understood. We hypothesized that the fungal cell wall would play an important role in determining the competitive fitness of species in the mammalian GI tract. To test this hypothesis, we generated a systematic collection of isogenic cell wall mutants and measured their fitness in the mouse GI tract via quantitative competition assays. Whereas a large variation in competitive fitness was found among mutants, no correlation was observed between GI fitness and total levels of individual cell wall components. Similar results were obtained in a set of distantly-related species, suggesting that total amounts of individual cell wall components do not determine the ability of fungi to colonize the GI tract. We then subjected this collection of strains and species to an extensive quantitative phenotypic profiling in search for features that might be responsible for their differences in GI fitness, but found no association with the ability to grow in GI-mimicking and stressful environments or with and virulence. The most significant association with GI fitness was found to be the strength of signaling through the Dectin-1 receptor. Using a quantitative assay to measure the amount of exposed β-glucan on the surface of fungal cells, we found this parameter, unlike total β-glucan levels, to be strongly predictive of competitive fitness in the mouse GI tract. These data suggest that fungal cell wall architecture, more so than its crude composition, critically determines the ability of fungi to colonize the mammalian GI tract. In particular, recognition of exposed β-glucan by Dectin-1 receptor appears to severely limit GI fitness and hence represents a promising target to reduce fungal colonization in patients at risks of systemic candidiasis.
每年导致约40万例系统性真菌感染，相关死亡率为46%-75%。人类胃肠道是该菌属最大的天然储存库，也是系统性真菌感染的主要来源。然而，控制该菌属在胃肠道定殖的因素尚未完全明确。我们推测真菌细胞壁在决定该菌属在哺乳动物胃肠道中的竞争适应性方面将发挥重要作用。为验证这一假设，我们系统构建了一组同基因的真菌细胞壁突变体，并通过定量竞争试验测定它们在小鼠胃肠道中的适应性。虽然突变体之间的竞争适应性存在很大差异，但未观察到胃肠道适应性与单个细胞壁成分的总量之间存在相关性。在一组亲缘关系较远的该菌属物种中也得到了类似结果，表明单个细胞壁成分的总量并不能决定真菌在胃肠道定殖的能力。然后，我们对这组该菌属菌株和物种进行了广泛的定量表型分析，以寻找可能导致它们在胃肠道适应性上存在差异的特征，但未发现与在模拟胃肠道和应激环境中的生长能力或与毒力有关联。与胃肠道适应性最显著的关联是通过Dectin-1受体的信号传导强度。通过定量测定真菌细胞表面暴露的β-葡聚糖量，我们发现该参数与总β-葡聚糖水平不同，能强烈预测在小鼠胃肠道中的竞争适应性。这些数据表明，真菌细胞壁结构比其粗略组成更关键地决定了真菌在哺乳动物胃肠道定殖的能力。特别是，Dectin-1受体对暴露的β-葡聚糖的识别似乎严重限制了该菌属在胃肠道的适应性，因此是降低系统性念珠菌病风险患者真菌定殖的一个有前景的靶点。
