噬菌体疗法在胞内病原菌治疗中的挑战与思考

doi:10.12211/2096-8280.2023-002

合成生物学 ›› 2023, Vol. 4 ›› Issue (4): 676-689.DOI: 10.12211/2096-8280.2023-002

噬菌体疗法在胞内病原菌治疗中的挑战与思考

王凯¹, 张婉², 黄云海³, 张立新³, 娄春波¹

^1.中国科学院深圳先进技术研究院，细胞与基因线路设计中心，广东深圳 518000
^2.上海药明生物技术有限公司，上海 200131
^3.华东理工大学生物工程学院，生物反应器工程国家重点实验室，上海 200237

收稿日期:2023-01-01 修回日期:2023-02-27 出版日期:2023-08-31 发布日期:2023-09-14
通讯作者: 张立新,娄春波
作者简介:王凯（1995—），男，硕士研究生。研究方向为靶向巨噬细胞胞内结核杆菌的人工噬菌体设计。E-mail：380571165@qq.com
张立新（1968—），男，研究员，博士生导师。研究方向为生物工程；生物化工；生物与医药（生物工程领域）；采用互动高通量技术筛选活性微生物及其次生代谢产物；利用合成生物学手段提高重要活性微生物次级代谢产物产量等。E-mail：lxzhang@ecust.edu.cn
娄春波（1981—），男，研究员，博士生导师。研究方向为人工生命体设计；哺乳细胞基因线路设计与应用；有限代繁殖的病原菌疫苗；人工生命体的安全性与可控性；靶向巨噬细胞胞内结核杆菌的人工噬菌体设计。E-mail：cb.lou@siat.ac.cn
基金资助:
国家自然科学基金(31720103901);国家重点研发计划(2020YFA0907800);“111”计划(B18022);国家自然科学基金青年科学基金(32100145)

Application of phage therapy in the treatment of intracellular pathogens

Kai WANG¹, Wan ZHANG², Yunhai HUANG³, Lixin ZHANG³, Chunbo LOU¹

^1.Cell and Gene Circuit Design Center，Shenzhen Institute of Advanced Technology，Chinese Academy of Sciences，Shenzhen 518000，Guangdong，China
^2.WuXi Biologics （Shanghai） Co. ，Ltd，Shanghai 200131，China
^3.State key Laboratory of Bioreactor Engineering，School of Biological Engineering，East China University of Science and Technology，Shanghai 200237，China

Received:2023-01-01 Revised:2023-02-27 Online:2023-08-31 Published:2023-09-14
Contact: Lixin ZHANG, Chunbo LOU

摘要/Abstract

摘要：

胞内病原菌是一类可以侵入并在哺乳动物细胞内生存的病原菌，它们可以调节宿主细胞内环境以便自身繁衍扩散。由于细胞膜等结构的保护，胞内病原菌在细胞内不容易被药物接触到，且容易积累耐药性，使得胞内病原菌的治疗成为一个悬而未决的难题，亟需新的治疗方法。噬菌体疗法是利用噬菌体裂解细菌治疗病原菌感染的手段。由于其不会对动物细胞产生危害，已经被广泛用于治疗病原细菌的胞外感染，同时为胞内病原菌的治疗提供了行之有效的新思路。本文介绍了细胞内病原体侵入和定居在真核细胞中的策略，以及它们对抗生素的抗性机制。噬菌体疗法具有独特的杀菌机制及突出的优势，因此噬菌体疗法在处理细胞内病原体特别是耐药病原体方面有巨大潜力。但噬菌体疗法在治疗细胞内病原体方面的应用仍面临许多挑战，如噬菌体不能轻易穿过真核细胞膜与细胞内病原体接触。最后，讨论了噬菌体疗法在治疗细胞内耐药病原体方面可能的发展方向。未来需解决噬菌体入胞难题，通过细胞穿透肽修饰或纳米材料修饰，使噬菌体能够有效地进入真核细胞。在此基础上，可以对噬菌体本身进行改造，获得杀菌效果更强的重组噬菌体，并进一步挖掘包括温和噬菌体在内的噬菌体资源。

关键词: 胞内病原菌, 耐药性, 噬菌体, 噬菌体疗法, 跨膜运输

Abstract:

Intracellular pathogens are a class of pathogens that can invade eukaryotic cells and survive in cells. After entering the host cell, they can regulate the intracellular environment so as to facilitate their own reproduction and spread, while the host's cell membrane and other structures will protect intracellular pathogens from being attacked by antibiotics, resulting in treatment failure. the increasingly serious drug resistance of intracellular pathogens makes the problem more difficult. It is necessary to explore bacteriostatic methods other than antibiotics, and phage therapy is a good choice. Bacteriophages have been used to treat bacterial infections as early as their discovery because they can effectively kill extracellular pathogens. However, phage therapy to deal with intracellular pathogens is still in the exploratory stage. In this review, we introduce the strategies of intracellular pathogens invading and settling in eukaryotic cells, as well as the mechanism of their resistance to antibiotics. It shows the unique bactericidal mechanism of phage therapy and its outstanding advantages, and the great potential of phage therapy in dealing with intracellular pathogens, especially drug-resistant pathogens. Of course, the application of phage therapy in the treatment of intracellular pathogens still faces many challenges, such as the fact that bacteriophages can not easily pass through the eukaryotic cell membrane to contact with intracellular pathogens. Finally, we discussed the possible development direction of bacteriophage therapy in the treatment of intracellular drug-resistant pathogens. We believe that first of all, we must adopt the "Trojan horse" strategy,cell-penetrating peptides modification or nanomaterial modification to make it possible for bacteriophages to enter eukaryotic cells efficiently. On this basis, the bacteriophage itself can be modified to obtain a recombinant bacteriophage with stronger bactericidal efficacy, and the bacteriophage resources, including mild bacteriophage, should be further explored. {L-End}

Key words: intracellular pathogens, antibiotic resistance, bacteriophage(phage), phage therapy, membrane translocation

中图分类号:

Q816

王凯, 张婉, 黄云海, 张立新, 娄春波. 噬菌体疗法在胞内病原菌治疗中的挑战与思考[J]. 合成生物学, 2023, 4(4): 676-689.

Kai WANG, Wan ZHANG, Yunhai HUANG, Lixin ZHANG, Chunbo LOU. Application of phage therapy in the treatment of intracellular pathogens[J]. Synthetic Biology Journal, 2023, 4(4): 676-689.

图/表 3

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细胞内病原菌	噬菌体	实验模型/细胞类型	文献来源	研究阶段
Chlamydia psittaci	phiCPG1	HeLa cells	Hsia et al, 2000^[83]	Preclinical Research
Staphylococcus aureus	M^Sa	Peritoneal mouse macrophages/mice	Capparelli et al, 2007^[84]	Preclinical Research
	MR-5	Peritoneal mouse macrophages	Kaur et al, 2014^[85]	Preclinical Research
	vB_SauM_JS25	Bovine Mammary Epithelial Cells (MAC-T)	Zhang et al, 2017^[86]	Preclinical Research
	MR-5 and MR-10	mice	Chhibber et al, 2018^[87]	Preclinical Research
	PP1493, PP1815, and PP1957	MG63 osteoblastic Cells	Kolenda et al, 2020^[88]	Preclinical Research
Burkholderia pseudomallei	C34	mice	Guang-Han et al, 2016^[89]	Preclinical Research
Escherichia coli	K1F	Urinary bladder epithelial cell line, T24 (HTB-4)	Møller-Olsen et al, 2018^[90]	Preclinical Research
	K1F	human cerebral microvascularendothelial cells (hCMEC)	Møller-Olsen et al, 2020^[91]	Preclinical Research
Klebsiella pneumoniae	KPO1K2	Peritoneal mouse macrophages	Singha et al, 2005^[92]	Preclinical Research
	KØ1, KØ2, KØ3, KØ4 and KØ5	mice	Chadha et al, 2017^[93]	Preclinical Research
M. tuberculosis /Mycobacterium avium	TM4	Mouse peritoneal macrophage cell line, RAW 264.7	Broxmeyer et al, 2002^[16]	Preclinical Research
Mycobacterium avium	TM4	mice	Danelishvili et al, 2006^[17]	Preclinical Research
M. tuberculosis	DS-A	pigs	Zemskova et al, 1991^[94]	Preclinical Research
	D29	mouse peritoneal macrophages	Peng et al, 2006^[95]	Preclinical Research
	D29	macrophages	Xiong et al, 2014^[96]	Preclinical Research
	D29	mice	Carrigy et al, 2017^[97]	Preclinical Research
	D29	Peritoneal mouse macrophages	Lapenkova et al, 2018^[98]	Preclinical Research
	D29	mice	Carrigy et al, 2019^[99]	Preclinical Research

细胞内病原菌	噬菌体	实验模型/细胞类型	文献来源	研究阶段
Chlamydia psittaci	phiCPG1	HeLa cells	Hsia et al, 2000^[83]	Preclinical Research
Staphylococcus aureus	M^Sa	Peritoneal mouse macrophages/mice	Capparelli et al, 2007^[84]	Preclinical Research
	MR-5	Peritoneal mouse macrophages	Kaur et al, 2014^[85]	Preclinical Research
	vB_SauM_JS25	Bovine Mammary Epithelial Cells (MAC-T)	Zhang et al, 2017^[86]	Preclinical Research
	MR-5 and MR-10	mice	Chhibber et al, 2018^[87]	Preclinical Research
	PP1493, PP1815, and PP1957	MG63 osteoblastic Cells	Kolenda et al, 2020^[88]	Preclinical Research
Burkholderia pseudomallei	C34	mice	Guang-Han et al, 2016^[89]	Preclinical Research
Escherichia coli	K1F	Urinary bladder epithelial cell line, T24 (HTB-4)	Møller-Olsen et al, 2018^[90]	Preclinical Research
	K1F	human cerebral microvascularendothelial cells (hCMEC)	Møller-Olsen et al, 2020^[91]	Preclinical Research
Klebsiella pneumoniae	KPO1K2	Peritoneal mouse macrophages	Singha et al, 2005^[92]	Preclinical Research
	KØ1, KØ2, KØ3, KØ4 and KØ5	mice	Chadha et al, 2017^[93]	Preclinical Research
M. tuberculosis /Mycobacterium avium	TM4	Mouse peritoneal macrophage cell line, RAW 264.7	Broxmeyer et al, 2002^[16]	Preclinical Research
Mycobacterium avium	TM4	mice	Danelishvili et al, 2006^[17]	Preclinical Research
M. tuberculosis	DS-A	pigs	Zemskova et al, 1991^[94]	Preclinical Research
	D29	mouse peritoneal macrophages	Peng et al, 2006^[95]	Preclinical Research
	D29	macrophages	Xiong et al, 2014^[96]	Preclinical Research
	D29	mice	Carrigy et al, 2017^[97]	Preclinical Research
	D29	Peritoneal mouse macrophages	Lapenkova et al, 2018^[98]	Preclinical Research
	D29	mice	Carrigy et al, 2019^[99]	Preclinical Research

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[3]	金交羽, 周佳海. Z-基因组的生物合成奥秘被揭示[J]. 合成生物学, 2022, 3(1): 1-5.
[4]	袁盛建, 马迎飞. 噬菌体合成生物学研究进展和应用[J]. 合成生物学, 2020, 1(6): 635-655.

噬菌体疗法在胞内病原菌治疗中的挑战与思考

Application of phage therapy in the treatment of intracellular pathogens

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