Interfaculty Institute of Microbiology and Infection Medicine, Infection Biology, University of Tübingen, Tübingen, Germany.
German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany.
Nature. 2018 Nov;563(7733):705-709. doi: 10.1038/s41586-018-0730-x. Epub 2018 Nov 21.
Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans. Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients. Previous vaccine development programs have not been successful. A large percentage of human antibodies against S. aureus target wall teichoic acid (WTA), a ribitol-phosphate (RboP) surface polymer modified with N-acetylglucosamine (GlcNAc). It is currently unknown whether the immune evasion capacities of MRSA are due to variation of dominant surface epitopes such as those associated with WTA. Here we show that a considerable proportion of the prominent healthcare-associated and livestock-associated MRSA clones CC5 and CC398, respectively, contain prophages that encode an alternative WTA glycosyltransferase. This enzyme, TarP, transfers GlcNAc to a different hydroxyl group of the WTA RboP than the standard enzyme TarS, with important consequences for immune recognition. TarP-glycosylated WTA elicits 7.5-40-fold lower levels of immunoglobulin G in mice than TarS-modified WTA. Consistent with this, human sera contained only low levels of antibodies against TarP-modified WTA. Notably, mice immunized with TarS-modified WTA were not protected against infection with tarP-expressing MRSA, indicating that TarP is crucial for the capacity of S. aureus to evade host defences. High-resolution structural analyses of TarP bound to WTA components and uridine diphosphate GlcNAc (UDP-GlcNAc) explain the mechanism of altered RboP glycosylation and form a template for targeted inhibition of TarP. Our study reveals an immune evasion strategy of S. aureus based on averting the immunogenicity of its dominant glycoantigen WTA. These results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defences.
耐甲氧西林金黄色葡萄球菌（MRSA）是一种常见的难以治疗的病原体，常导致人类致命感染。大多数人类都有针对金黄色葡萄球菌的抗体，但这些抗体高度可变，在免疫功能低下的患者中通常没有保护作用。以前的疫苗开发计划都没有成功。人类针对金黄色葡萄球菌的抗体很大一部分针对壁磷壁酸（WTA），这是一种经过 N-乙酰葡萄糖胺（GlcNAc）修饰的核糖醇磷酸（RboP）表面聚合物。目前尚不清楚 MRSA 的免疫逃逸能力是否归因于主导表面表位的变异，例如与 WTA 相关的表位。在这里，我们表明，大量的主要医疗保健相关和牲畜相关的 MRSA 克隆 CC5 和 CC398 分别含有编码替代 WTA 糖基转移酶的噬菌体。这种酶，TarP，将 GlcNAc 转移到 WTA RboP 的不同羟基上，而不是标准酶 TarS，这对免疫识别有重要影响。TarP 糖基化的 WTA 引发的免疫球蛋白 G 水平比 TarS 修饰的 WTA 低 7.5-40 倍。与此一致，人类血清中仅含有针对 TarP 修饰的 WTA 的低水平抗体。值得注意的是，用 TarS 修饰的 WTA 免疫的小鼠不能免受表达 tarP 的 MRSA 感染，表明 TarP 对于金黄色葡萄球菌逃避宿主防御至关重要。TarP 与 WTA 成分和尿苷二磷酸 N-乙酰葡萄糖胺（UDP-GlcNAc）结合的高分辨率结构分析解释了 RboP 糖基化改变的机制，并为靶向抑制 TarP 提供了模板。我们的研究揭示了金黄色葡萄球菌基于回避其主要糖抗原 WTA 的免疫原性的免疫逃逸策略。这些结果将有助于鉴定不变的金黄色葡萄球菌疫苗抗原，并可能使 TarP 抑制剂的开发成为使 MRSA 易受人体防御的新策略。
