由于人类宿主内过渡金属的稀缺性,真菌病原体已经进化出复杂的机制来在感染界面吸收和利用这些微量营养素。尽管人们相当关注铁和铜的获取机制及其在真菌适应性中的重要性,关于锰(Mn)在感染过程中的作用或真菌细胞实现Mn稳态的细胞机制的研究较少。这里,我们在经历Mn饥饿和过量的病原真菌白色念珠菌中进行了转录分析,以捕获由该金属调节的生物过程。我们发现锰稀缺性影响与真菌适应性相关的多种过程,包括宿主细胞的入侵和抗真菌敏感性。我们表明,Mn水平会影响铁和锌的丰度,从而强调金属之间的复杂串扰。MnNramp转运蛋白成员SMF12的删除,证实了它对锰吸收的贡献。smf12不能形成菌丝并损伤宿主细胞,对唑类表现出敏感性。我们发现未折叠的蛋白质反应(UPR),在锰限制下,可能被糖基化降低激活,当细胞从Mn饥饿的转移到Mn复制的培养基时,需要恢复生长。暴露于过量Mn的细胞的RNA-seq谱显示UPR也被激活。此外,绕过Mn毒性需要UPR信号轴Ire1-Hac1.总的来说,这项研究强调了Mn稳态在真菌毒力中的重要性,并全面提供了Mn在真菌病原体中调节的生物学功能。重要过渡金属如锰在生物系统中提供了相当大的功能,因为它们被用作许多催化酶的辅因子。锰的可利用性在人体内是非常有限的。因此,病原微生物已经进化出复杂的机制,在人类宿主体内吸收这种微量营养素,以维持它们的生长并引起感染。这里,我们采取了全面的方法来了解锰的可用性如何影响流行的真菌病原体的生物学,白色念珠菌.我们发现,这种病原体中的锰稳态可调节宿主感染所必需的不同生物过程,这突显了靶向真菌锰稳态对潜在抗真菌疗法开发的价值。
Due to the scarcity of transition metals within the human host, fungal pathogens have evolved sophisticated mechanisms to uptake and utilize these micronutrients at the infection interface. While considerable attention was turned to iron and copper acquisition mechanisms and their importance in fungal fitness, less was done regarding either the role of manganese (Mn) in infectious processes or the cellular mechanism by which fungal cells achieve their Mn-homeostasis. Here, we undertook transcriptional profiling in the pathogenic fungus Candida albicans experiencing both Mn starvation and excess to capture biological processes that are modulated by this metal. We uncovered that Mn scarcity influences diverse processes associated with fungal fitness including invasion of host cells and antifungal sensitivity. We show that Mn levels influence the abundance of iron and zinc emphasizing the complex crosstalk between metals. The deletion of SMF12, a member of Mn Nramp transporters, confirmed its contribution to Mn uptake. smf12 was unable to form hyphae and damage host cells and exhibited sensitivity to azoles. We found that the unfolded protein response (UPR), likely activated by decreased glycosylation under Mn limitation, was required to recover growth when cells were shifted from an Mn-starved to an Mn-repleted medium. RNA-seq profiling of cells exposed to Mn excess revealed that UPR was also activated. Furthermore, the UPR signaling axis Ire1-Hac1 was required to bypass Mn toxicity. Collectively, this study underscores the importance of Mn homeostasis in fungal virulence and comprehensively provides a portrait of biological functions that are modulated by Mn in a fungal pathogen.
OBJECTIVE: Transition metals such as manganese provide considerable functionality across biological systems as they are used as cofactors for many catalytic enzymes. The availability of manganese is very limited inside the human body. Consequently, pathogenic microbes have evolved sophisticated mechanisms to uptake this micronutrient inside the human host to sustain their growth and cause infections. Here, we undertook a comprehensive approach to understand how manganese availability impacts the biology of the prevalent fungal pathogen, Candida albicans. We uncovered that manganese homeostasis in this pathogen modulates different biological processes that are essential for host infection which underscores the value of targeting fungal manganese homeostasis for potential antifungal therapeutics development.