The basidiomycetous fungal pathogen Cryptococcus neoformans is adapted to survive challenges in the soil and environment and within the unique setting of the mammalian host. A C. neoformans mutant was isolated with enhanced virulence in a soil amoeba model that nevertheless exhibits dramatically reduced growth at mammalian body temperature (37 degrees C). This mutant phenotype results from an insertion in the ECA1 gene, which encodes a sarcoplasmic/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA)-type calcium pump. Infection in murine macrophages, amoebae (Acanthamoeba castellanii), nematodes (Caenorhabditis elegans), and wax moth (Galleria mellonella) larvae revealed that the eca1 mutants are virulent or hypervirulent at permissive growth temperatures but attenuated at 37 degrees C. Deletion mutants lacking the entire ECA1 gene were also hypersensitive to the calcineurin inhibitors cyclosporin and FK506 and to ER and osmotic stresses. An eca1Delta cna1Delta mutant lacking both Eca1 and the calcineurin catalytic subunit was more sensitive to high temperature and ER stresses than the single mutants and exhibited reduced survival in C. elegans and attenuated virulence towards wax moth larvae at temperatures that permit normal growth in vitro. Eca1 is likely involved in maintaining ER function, thus contributing to stress tolerance and virulence acting in parallel with Ca2+-calcineurin signaling.

译文

担子菌真菌病原体新隐球菌适合在土壤和环境中以及在哺乳动物宿主的独特环境中生存。在土壤变形虫模型中分离了具有增强毒力的新孢子虫突变体,该模型在哺乳动物体温 (37摄氏度) 下表现出显着降低的生长。这种突变表型是由ECA1基因插入的结果,该基因编码肌浆/内质网 (ER) ca2-atpase (SERCA) 型钙泵。鼠巨噬细胞,变形虫 (Acanthamoeba castellanii),线虫 (秀丽隐杆线虫) 和蜡蛾 (Galleria mellonella) 幼虫的感染表明,eca1突变体在允许的生长温度下具有毒性或高毒性,但在37摄氏度时减弱。缺乏整个ECA1基因的缺失突变体也对钙调神经磷酸酶抑制剂环孢菌素和FK506以及ER和渗透胁迫过敏。缺乏Eca1和钙调神经磷酸酶催化亚基的eca1Delta cna1Delta突变体比单个突变体对高温和ER胁迫更敏感,并且在秀丽隐杆线虫的存活率降低,并且在允许体外正常生长的温度下对蜡蛾幼虫的毒力减弱。Eca1可能参与维持ER功能,从而与Ca2-钙调神经磷酸酶信号传导平行促进应激耐受性和毒力。

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