Mp1p Is a Virulence Factor in Talaromyces (Penicillium) marneffei

BackgroundTalaromyces marneffei is an opportunistic dimorphic fungus prevalent in Southeast Asia. We previously demonstrated that Mp1p is an immunogenic surface and secretory mannoprotein of T. marneffei. Since Mp1p is a surface protein that can generate protective immunity, we hypothesized that Mp1p and/or its homologs are virulence factors.Methodology/Principal FindingsWe examined the pathogenic roles of Mp1p and its homologs in a mouse model. All mice died 21 and 30 days after challenge with wild-type T. marneffei PM1 and MP1 complemented mutant respectively. None of the mice died 60 days after challenge with MP1 knockout mutant (PMP1 knockdown mutant (PMPLP1 to MPLP13 knockdown mutants, suggesting that only Mp1p plays a significant role in virulence. The mean fungal loads of PM1 and MP1 complemented mutant in the liver, lung, kidney and spleen were significantly higher than those of the MP1 knockout mutant. Similarly, the mean load of PM1 in the liver, lung and spleen were significantly higher than that of the MP1 knockdown mutant. Histopathological studies showed an abundance of yeast in the kidney, spleen, liver and lung with more marked hepatic and splenic necrosis in mice challenged with PM1 compared to MP1 knockout and MP1 knockdown mutants. Likewise, a higher abundance of yeast was observed in the liver and spleen of mice challenged with MP1 complemented mutant compared to MP1 knockout mutant. PM1 and MP1 complemented mutant survived significantly better than MP1 knockout mutant in macrophages at 48 hours (PPichia pastoris GS115-MP1 in the liver (PConclusions/SignificanceMp1p is a key virulence factor of T. marneffei. Mp1p mediates virulence by improving the survival of T. marneffei in macrophages.背景：马尔尼菲篮状菌（Talaromyces marneffei）是一种流行于东南亚的机会致病二态性真菌。本团队此前的研究证实，Mp1p是马尔尼菲篮状菌的免疫原性表面及分泌型甘露糖蛋白。鉴于Mp1p作为表面蛋白可诱导保护性免疫，我们推测Mp1p及其同源蛋白为该菌的毒力因子。 研究方法与主要结果：我们在小鼠模型中验证了Mp1p及其同源蛋白的致病作用。野生型马尔尼菲篮状菌PM1株与MP1基因互补突变株分别在攻毒后21天、30天导致全部受试小鼠死亡；使用MP1基因敲除突变株攻毒的小鼠在60天观察期内均未出现死亡，PMP1基因敲低突变株（涵盖PMPLP1至MPLP13敲低突变体）组亦未出现小鼠死亡，提示仅Mp1p在该菌毒力发挥中起到关键作用。 野生型PM1株与MP1基因互补突变株在肝脏、肺脏、肾脏及脾脏中的平均真菌载量均显著高于MP1基因敲除突变株。类似地，PM1株在肝脏、肺脏及脾脏中的平均真菌载量亦显著高于MP1基因敲低突变株。组织病理学研究显示，PM1株攻毒组小鼠的肾脏、脾脏、肝脏及肺脏中酵母样菌体大量富集，且相较于MP1基因敲除与敲低突变株组，其肝脏与脾脏的坏死程度更为显著。同样，MP1基因互补突变株攻毒组小鼠的肝脏与脾脏中酵母样菌体丰度亦高于MP1基因敲除突变株组。在感染后48小时，PM1株与MP1基因互补突变株在巨噬细胞中的存活率显著高于MP1基因敲除突变株；毕赤酵母（Pichia pastoris）GS115-MP1在肝脏中的相关检测结果（原文此处存在输入截断）亦显示类似趋势。 研究结论与意义：Mp1p是马尔尼菲篮状菌的关键毒力因子。Mp1p通过提升马尔尼菲篮状菌在巨噬细胞中的存活能力来介导其致病过程。