Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA.
Department of Pediatrics, Section of Developmental Biology, University of Colorado School of Medicine, Aurora, CO, USA.
Sci Adv. 2024 May 31;10(22):eadn7848. doi: 10.1126/sciadv.adn7848. Epub 2024 May 29.
[group B (GBS)] is a leading cause of neonatal meningitis, with late-onset disease (LOD) occurring after gastrointestinal tract colonization in infants. Bacterial membrane lipids are essential for host-pathogen interactions, and the functions of glycolipids are yet to be fully elucidated. GBS synthesizes three major glycolipids: glucosyl-diacylglycerol (Glc-DAG), diglucosyl-DAG (Glc-DAG), and lysyl-Glc-DAG (Lys-Glc-DAG). Here, we identify the enzyme, IagB, as responsible for biosynthesis of Glc-DAG, the precursor for the two other glycolipids in GBS. To examine the collective role of glycolipids to GBS virulence, we adapted a murine model of neonatal meningitis to simulate LOD. The GBS∆ mutant traversed the gut-epithelial barrier comparable to wild type but was severely attenuated in bloodstream survival, resulting in decreased bacterial loads in the brain. The GBS∆ mutant was more susceptible to neutrophil killing and membrane targeting by host antimicrobial peptides. This work reveals an unexplored function of GBS glycolipids with their ability to protect the bacterial cell from host antimicrobial killing.
[B 组链球菌 (GBS)]是导致新生儿脑膜炎的主要原因，其迟发性疾病 (LOD)发生在婴儿胃肠道定植后。细菌膜脂质对于宿主-病原体相互作用至关重要，糖脂的功能仍有待充分阐明。GBS 合成三种主要的糖脂：葡萄糖二酰基甘油 (Glc-DAG)、双葡萄糖二酰基甘油 (Glc-DAG) 和赖氨酸葡萄糖二酰基甘油 (Lys-Glc-DAG)。在这里，我们确定了酶 IagB 负责 Glc-DAG 的生物合成，这是 GBS 中另外两种糖脂的前体。为了研究糖脂对 GBS 毒力的综合作用，我们适应了一种新生儿脑膜炎的小鼠模型来模拟 LOD。与野生型相比，GBS∆突变体能够穿透肠道上皮屏障，但在血液中存活能力严重减弱，导致大脑中的细菌载量减少。GBS∆突变体更容易被中性粒细胞杀伤，并被宿主抗菌肽靶向细胞膜。这项工作揭示了 GBS 糖脂的一个未被探索的功能，即其能够保护细菌细胞免受宿主抗菌肽的杀伤。
