Medical Microbiology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Bioessays. 2019 Oct;41(10):e1900074. doi: 10.1002/bies.201900074. Epub 2019 Aug 26.
The human immune system can directly lyse invading micro-organisms and aberrant host cells by generating pores in the cell envelope, called membrane attack complexes (MACs). Recent studies using single-particle cryoelectron microscopy have revealed that the MAC is an asymmetric, flexible pore and have provided a structural basis on how the MAC ruptures single lipid membranes. Despite these insights, it remains unclear how the MAC ruptures the composite cell envelope of Gram-negative bacteria. Recent functional studies on Gram-negative bacteria elucidate that local assembly of MAC pores by surface-bound C5 convertase enzymes is essential to stably insert these pores into the bacterial outer membrane (OM). These convertase-generated MAC pores can subsequently efficiently damage the bacterial inner membrane (IM), which is essential for bacterial killing. This review summarizes these recent insights of MAC assembly and discusses how MAC pores kill Gram-negative bacteria. Furthermore, this review elaborates on how MAC-dependent OM damage could lead to IM destabilization, which is currently not well understood. A better understanding on how MAC pores kill bacteria could facilitate the future development of novel strategies to treat infections with Gram-negative bacteria.
人体免疫系统可以通过在细胞包膜上生成孔，即膜攻击复合物（MAC），直接溶解入侵的微生物和异常的宿主细胞。最近使用单颗粒冷冻电子显微镜的研究揭示了 MAC 是一种不对称的、灵活的孔，并提供了 MAC 如何破坏单层脂质膜的结构基础。尽管有了这些见解，但 MAC 如何破坏革兰氏阴性菌的复合细胞包膜仍不清楚。最近对革兰氏阴性菌的功能研究阐明了表面结合的 C5 转化酶酶对 MAC 孔的局部组装对于将这些孔稳定地插入细菌外膜（OM）至关重要。这些由转化酶生成的 MAC 孔随后可以有效地损伤细菌内膜（IM），这对于细菌杀伤至关重要。这篇综述总结了 MAC 组装的这些最新见解，并讨论了 MAC 孔如何杀死革兰氏阴性菌。此外，本综述阐述了 MAC 依赖性 OM 损伤如何导致 IM 失稳，目前对此知之甚少。更好地了解 MAC 孔如何杀死细菌可以促进未来开发治疗革兰氏阴性菌感染的新策略。
