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可溶性 MAC 主要从对补体成分 C5 具有强大转化作用的 MAC 抗性细菌中释放出来。

Soluble MAC is primarily released from MAC-resistant bacteria that potently convert complement component C5.

机构信息

Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands.

Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, Netherlands.

出版信息

Elife. 2022 Aug 10;11:e77503. doi: 10.7554/eLife.77503.

DOI:10.7554/eLife.77503
PMID:35947526
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9402229/
Abstract

The membrane attack complex (MAC or C5b-9) is an important effector of the immune system to kill invading microbes. MAC formation is initiated when complement enzymes on the bacterial surface convert complement component C5 into C5b. Although the MAC is a membrane-inserted complex, soluble forms of MAC (sMAC), or terminal complement complex (TCC), are often detected in sera of patients suffering from infections. Consequently, sMAC has been proposed as a biomarker, but it remains unclear when and how it is formed during infections. Here, we studied mechanisms of MAC formation on different Gram-negative and Gram-positive bacteria and found that sMAC is primarily formed in human serum by bacteria resistant to MAC-dependent killing. Surprisingly, C5 was converted into C5b more potently by MAC-resistant compared to MAC-sensitive strains. In addition, we found that MAC precursors are released from the surface of MAC-resistant bacteria during MAC assembly. Although release of MAC precursors from bacteria induced lysis of bystander human erythrocytes, serum regulators vitronectin (Vn) and clusterin (Clu) can prevent this. Combining size exclusion chromatography with mass spectrometry profiling, we show that sMAC released from bacteria in serum is a heterogeneous mixture of complexes composed of C5b-8, up to three copies of C9 and multiple copies of Vn and Clu. Altogether, our data provide molecular insight into how sMAC is generated during bacterial infections. This fundamental knowledge could form the basis for exploring the use of sMAC as biomarker.

摘要

膜攻击复合物（MAC 或 C5b-9）是免疫系统杀死入侵微生物的重要效应物。当补体酶在细菌表面将补体成分 C5 转化为 C5b 时，MAC 就会形成。尽管 MAC 是一种插入膜的复合物，但可溶性 MAC（sMAC）或末端补体复合物（TCC）通常在感染患者的血清中被检测到。因此，sMAC 被提议作为一种生物标志物，但它在感染期间何时以及如何形成尚不清楚。在这里，我们研究了不同革兰氏阴性和革兰氏阳性细菌上 MAC 形成的机制，发现 sMAC 主要是由对 MAC 依赖性杀伤有抗性的细菌在人血清中形成的。令人惊讶的是，与 MAC 敏感株相比，MAC 抗性株更有效地将 C5 转化为 C5b。此外，我们发现 MAC 前体在 MAC 组装过程中从 MAC 抗性细菌表面释放出来。尽管从 MAC 抗性细菌释放 MAC 前体诱导旁观者人红细胞裂解，但血清调节剂 vitronectin (Vn) 和 clusterin (Clu) 可以阻止这种情况。结合排阻色谱和质谱分析，我们表明从血清中细菌释放的 sMAC 是由 C5b-8、多达三个 C9 拷贝和多个 Vn 和 Clu 拷贝组成的复合物的不均匀混合物。总的来说，我们的数据提供了关于 sMAC 如何在细菌感染过程中产生的分子见解。这些基本知识可以为探索 sMAC 作为生物标志物的用途奠定基础。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a85/9402229/ad3370b8e912/elife-77503-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a85/9402229/b185ba7c05c9/elife-77503-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a85/9402229/9ab94e69b79d/elife-77503-fig1-figsupp2.jpg
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