da Silva Ronni A G, Karlyshev Andrey V, Oldfield Neil J, Wooldridge Karl G, Bayliss Christopher D, Ryan Ali, Griffin Ruth
Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom.
School of Life Sciences, Pharmacy and Chemistry, Kingston University, Kingston upon Thames, United Kingdom.
Front Microbiol. 2019 Dec 19;10:2847. doi: 10.3389/fmicb.2019.02847. eCollection 2019.
Meningococcal lipoprotein, Factor H binding protein (FHbp), is the sole antigen of the Trumenba vaccine (Pfizer) and one of four antigens of the Bexsero vaccine (GSK) targeting serogroup B isolates. Lipidation of FHbp is assumed to occur for all isolates. We show in the majority of a collection of United Kingdom isolates (1742/1895) non-synonymous single nucleotide polymorphisms (SNPs) in the signal peptide (SP) of FHbp. A single SNP, common to all, alters a polar amino acid that abolishes processing: lipidation and SP cleavage. Whilst some of the FHbp precursor is retained in the cytoplasm due to reduced binding to SecA, remarkably some is translocated and further surface-localized by Slam. Thus we show Slam is not lipoprotein-specific. In a panel of isolates tested, the overall reduced surface localization of the precursor FHbp, compared to isolates with an intact SP, corresponded with decreased susceptibility to antibody-mediated killing. Our findings shed new light on the canonical pathway for lipoprotein processing and translocation of important relevance for lipoprotein-based vaccines in development and in particular for Trumenba.
脑膜炎球菌脂蛋白，即因子H结合蛋白（FHbp），是Trumenba疫苗（辉瑞公司）的唯一抗原，也是Bexsero疫苗（葛兰素史克公司）针对B群分离株的四种抗原之一。假定所有分离株都会发生FHbp的脂化。我们发现，在英国收集的大多数分离株（1742/1895）中，FHbp信号肽（SP）存在非同义单核苷酸多态性（SNP）。所有分离株都存在一个共同的单核苷酸多态性，它改变了一个极性氨基酸，从而消除了加工过程：脂化和信号肽切割。虽然部分FHbp前体由于与SecA的结合减少而保留在细胞质中，但值得注意的是，有些前体通过Slam转运并进一步定位到表面。因此我们证明Slam并非脂蛋白特异性的。在一组测试的分离株中，与信号肽完整的分离株相比，前体FHbp的整体表面定位减少，这与抗体介导杀伤的敏感性降低相对应。我们的研究结果为脂蛋白加工和转运的经典途径提供了新的见解，这对于正在研发的基于脂蛋白的疫苗，特别是Trumenba疫苗具有重要意义。
