Immunomimetic Designer Cells Protect Mice from MRSA Infection.
Immunomimetic Designer Cells Protect Mice from MRSA Infection.
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DOI：
10.1016/j.cell.2018.05.039
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发表时间：
2018-07-12
期刊：
影响因子：
64.5
通讯作者：
Fussenegger M
中科院分区：
文献类型：
--
作者：
Liu Y;Bai P;Woischnig AK;Charpin-El Hamri G;Ye H;Folcher M;Xie M;Khanna N;Fussenegger M
许多社区和医院获得性细菌感染是由耐药性病原体引起的。耐甲氧西林金黄色葡萄球菌（MRSA）使人类易患难以根除的侵入性感染。我们设计了一个闭环基因网络，编程哺乳动物细胞自主检测和消除细菌感染。基因电路包含作为细菌传感器的人Toll样受体和驱动溶葡萄球菌酶（一种对金黄色葡萄球菌高度致命的溶菌酶）的可逆和可调节表达的合成启动子。具有这种遗传电路的免疫模拟设计细胞对活葡萄球菌表现出快速和强大的感测和破坏动力学。当在小鼠的异物感染模型中进行测试时，微囊化细胞植入物预防了嗜酸性MRSA感染，并将MRSA生物膜形成减少了91%。值得注意的是，该系统实现了急性MRSA感染的100%治愈率，而常规万古霉素治疗失败。这些结果表明，免疫模拟设计细胞可以为后抗生素时代的病原性感染的早期检测、预防和治愈提供治疗方法。具有细菌感测和破坏驱动的闭环基因网络通过血液生物标志物直接诊断植入物相关感染体内MRSA感染的早期预防以及生物膜形成治疗急性MRSA感染作为抗生素治疗的替代方法具有合成基因电路的包封哺乳动物细胞感测和响应MRSA感染可以提供潜在的预防，诊断，或医疗植入物相关感染的治疗选择。
Many community- and hospital-acquired bacterial infections are caused by antibiotic-resistant pathogens. Methicillin-resistant Staphylococcus aureus (MRSA) predisposes humans to invasive infections that are difficult to eradicate. We designed a closed-loop gene network programming mammalian cells to autonomously detect and eliminate bacterial infections. The genetic circuit contains human Toll-like receptors as the bacterial sensor and a synthetic promoter driving reversible and adjustable expression of lysostaphin, a bacteriolytic enzyme highly lethal to S. aureus. Immunomimetic designer cells harboring this genetic circuit exhibited fast and robust sense-and-destroy kinetics against live staphylococci. When tested in a foreign-body infection model in mice, microencapsulated cell implants prevented planktonic MRSA infection and reduced MRSA biofilm formation by 91%. Notably, this system achieved a 100% cure rate of acute MRSA infections, whereas conventional vancomycin treatment failed. These results suggest that immunomimetic designer cells could offer a therapeutic approach for early detection, prevention, and cure of pathogenic infections in the post-antibiotic era. A closed-loop gene network with bacterial sense-and-destroy actuation Direct diagnosis of implant-associated infections through blood biomarkers Early prevention of MRSA infection, as well as biofilm formation, in vivo Curing acute MRSA infections as an alternative to antibiotic therapy Encapsulated mammalian cells with a synthetic gene circuit to sense and respond to MRSA infection could provide potential prophylactic, diagnostic, or therapeutic options for medical implant-associated infections.
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影响因子：
8.8
作者：
Godefroy E;Gallois A;Idoyaga J;Merad M;Tung N;Monu N;Saenger Y;Fu Y;Ravindran R;Pulendran B;Jotereau F;Trombetta S;Bhardwaj N
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作者：
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作者：
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通讯作者：
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影响因子：
16
作者：
Auslaender, David;Auslaender, Simon;Fussenegger, Martin
通讯作者：
Fussenegger, Martin