Diao Jingyu, Bouwman Catrien, Yan Donghong, Kang Jing, Katakam Anand K, Liu Peter, Pantua Homer, Abbas Alexander R, Nickerson Nicholas N, Austin Cary, Reichelt Mike, Sandoval Wendy, Xu Min, Whitfield Chris, Kapadia Sharookh B
Department of Infectious Diseases, Genentech, South San Francisco, California, USA.
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
mBio. 2017 May 23;8(3):e00603-17. doi: 10.1128/mBio.00603-17.
Murein lipoprotein (Lpp) and peptidoglycan-associated lipoprotein (Pal) are major outer membrane lipoproteins in Their roles in cell-envelope integrity have been documented in laboratory strains, and while Lpp has been linked to serum resistance , the underlying mechanism has not been established. Here, and mutants of uropathogenic strain CFT073 showed reduced survival in a mouse bacteremia model, but only the mutant was sensitive to serum killing The peptidoglycan-bound Lpp form was specifically required for preventing complement-mediated bacterial lysis and complement-mediated clearance Compared to the wild-type strain, the mutant had impaired K2 capsular polysaccharide production and was unable to respond to exposure to serum by elevating capsular polysaccharide amounts. These properties correlated with altered cellular distribution of KpsD, the predicted outer membrane translocon for "group 2" capsular polysaccharides. We identified a novel Lpp-dependent association between functional KpsD and peptidoglycan, highlighting important interplay between cell envelope components required for resistance to complement-mediated lysis in uropathogenic isolates. Uropathogenic (UPEC) isolates represent a significant cause of nosocomial urinary tract and bloodstream infections. Many UPEC isolates are resistant to serum killing. Here, we show that a major cell-envelope lipoprotein (murein lipoprotein) is required for serum resistance and for complement-mediated bacterial clearance This is mediated, in part, through a novel mechanism by which murein lipoprotein affects the proper assembly of a key component of the machinery involved in production of "group 2" capsules. The absence of murein lipoprotein results in impaired production of the capsule layer, a known participant in complement resistance. These results demonstrate an important role for murein lipoprotein in complex interactions between different outer membrane biogenesis pathways and further highlight the importance of lipoprotein assembly and transport in bacterial pathogenesis.
鼠李糖脂蛋白（Lpp）和肽聚糖相关脂蛋白（Pal）是大肠杆菌主要的外膜脂蛋白。它们在细胞包膜完整性方面的作用已在实验室菌株中得到证实，虽然Lpp与血清抗性有关，但其潜在机制尚未明确。在这里，尿路致病性大肠杆菌菌株CFT073的lpp和pal突变体在小鼠菌血症模型中的存活率降低，但只有pal突变体对血清杀伤敏感。肽聚糖结合形式的Lpp对于防止补体介导的细菌裂解和补体介导的清除是特别必需的。与野生型菌株相比，pal突变体的K2荚膜多糖产生受损，并且在暴露于血清时无法通过增加荚膜多糖量做出反应。这些特性与KpsD（预测的“2组”荚膜多糖外膜转运体）的细胞分布改变相关。我们确定了功能性KpsD与肽聚糖之间一种新的Lpp依赖性关联，突出了尿路致病性大肠杆菌分离株中抵抗补体介导裂解所需的细胞包膜成分之间的重要相互作用。尿路致病性大肠杆菌（UPEC）分离株是医院获得性尿路感染和血流感染的重要原因。许多UPEC分离株对血清杀伤具有抗性。在这里，我们表明一种主要的细胞包膜脂蛋白（鼠李糖脂蛋白）对于血清抗性和补体介导的细菌清除是必需的。这部分是通过一种新机制介导的，即鼠李糖脂蛋白影响参与“2组”荚膜产生的关键成分的正确组装。鼠李糖脂蛋白的缺失导致荚膜层产生受损，荚膜层是已知的补体抗性参与者。这些结果证明了鼠李糖脂蛋白在不同外膜生物合成途径之间复杂相互作用中的重要作用，并进一步突出了脂蛋白组装和转运在细菌发病机制中的重要性。
