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首页> 外文期刊>Eukaryotic cell >Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus
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Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus

机译：钙调神经磷酸酶控制烟曲霉的生长，形态和致病性

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Calcineurin is implicated in a myriad of human diseases as well as homeostasis and virulence in several major human pathogenic microorganisms. The fungus Aspergillus fumigatus is a leading cause of infectious death in the rapidly expanding immunocompromised patient population. Current antifungal treatments for invasive aspergillosis are often ineffective, and novel therapeutic approaches are urgently needed. We demonstrate that a mutant of A. fumigatus lacking the calcineurin A (cnaA) catalytic subunit exhibited defective hyphal morphology related to apical extension and polarized growth, which resulted in drastically decreased filamentation. The ΔcnaA mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the ΔcnaA mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the ΔcnaA mutant in several distinct animal models with different types of immunosuppression and inoculum delivery led to a profound attenuation of pathogenicity compared to infection with the wild-type and complemented strains. Lung tissue from animals infected with the ΔcnaA mutant showed a complete absence of hyphae, in contrast to tissue from animals infected with the wild-type and complemented strains. Quantitative fungal burden and pulmonary infarct scoring confirmed these findings. Our results support the clinical observation that substantially decreasing fungal growth can prevent disease establishment and decrease mortality. Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention.
机译：钙调神经磷酸酶与多种人类疾病以及几种主要的人类致病微生物的体内稳态和毒力有关。真菌烟曲霉是迅速增长的免疫功能低下患者人群中传染性死亡的主要原因。当前用于侵袭性曲霉病的抗真菌治疗通常无效，并且迫切需要新的治疗方法。我们证明了 A的突变体。缺乏钙调神经磷酸酶A（ cnaA ）催化亚基的烟熏菌表现出与根尖延伸和极化生长有关的菌丝形态缺陷，从而导致丝化作用大大降低。 Δ cnaA 突变体缺乏野生型和互补型菌株所见的入侵菌丝的广泛晶格。孢子的形成也受到Δ cnaA 突变体的影响，包括形态分生孢子缺陷，表面无杆状小孢子，并且分离物的存在增加了产生长分生孢子链的能力。与野生型和互补型菌株感染相比，在几种具有不同类型的免疫抑制和接种物递送的不同动物模型中，Δ cnaA 突变体的感染导致致病性大大降低。与感染野生型和互补菌株的动物组织相比，感染Δ cnaA 突变动物的肺组织显示完全没有菌丝。定量的真菌负担和肺梗塞评分证实了这些发现。我们的结果支持临床观察，即真菌生长的大幅减少可以预防疾病的发生并降低死亡率。我们的发现表明，钙调神经磷酸酶在几种致病真菌的毒性中似乎起着全球保守的作用，但在每种致病性真菌中均起着特殊作用，并且可以成为治疗干预的极佳靶标。

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