摘要
在后抗生素时代,噬菌体疗法是对抗耐药菌的重要候选武器。噬菌体具有丰富的多样性,其中的巨型噬菌体是一类基因组大于200 kb的噬菌体。由于其基因组容量大,功能基因类型丰富且排布分散。巨型噬菌体在生物学机制上具有许多特性,如拥有超大的噬菌体颗粒、独特的复制周期和结构(如核状区室、内体和长波浪卷曲尾丝)等。本文旨在对巨型噬菌体及其研究进展进行综述,重点剖析其生物学特点、基因组与进化、特殊的复制机制与结构,并探讨其在抗耐药菌感染、环境治理、水产养殖和生物防治等领域的应用潜力,为巨型噬菌体的相关研究和应用提供参考与启示。
随着抗生素的广泛使用,致病细菌的耐药性进化不断加速,耐药菌感染已成为当前临床治疗的一大挑
巨型噬菌体(jumbo phage)是基因组大小在200 kb以上的一类噬菌
巨型噬菌体较大的基因组赋予了其更大的潜力和更广阔的应用前景。其基因组结构(genome organization)、基因组中涵盖的基因类型等也展现出与普通噬菌体明显的区别。因此,研究巨型噬菌体有助于更好地理解噬菌体的生物学与进化。巨型噬菌体基因组中含有丰富的基因元件,这为噬菌体与宿主之间的相互作用研究提供了丰富的素材。对巨型噬菌体独特生物学特性的解析也将深化我们对噬菌体的认识。此外,巨型噬菌体在抗耐药菌感染、环境治理、食品安全和农牧业等领域展现出巨大的应用潜力,有望为相关难题的解决提供新的思路和方案。
1 巨型噬菌体的分离鉴定
巨型噬菌体的发现比普通噬菌体晚半个多世纪,其分离困难的主要原因在于其病毒粒子较大(平均头部直径约100 nm,尾长约200 nm),这阻碍了噬菌斑的形成,且可能在过滤去除细菌时被滤膜阻

图1 巨型噬菌体G的透射电镜形
Figure 1 Transmission electron microscope (TEM) morphology of jumbo phage
近年来,通过改进巨型噬菌体的分离、培养方法,如过滤时使用较大孔径的滤芯、采用更低琼脂糖浓度的半固体培养基等,以及借助迅速发展的宏基因组学技术、高通量测序技术、第三代测序技术、大片段DNA操纵技术等,巨型噬菌体的发现和分离鉴定进入了加速阶段,大量不同细菌的巨型噬菌体被发现并报道。2020年,Al-Shayeb

图2 巨型噬菌体基因组大小及数量分布
Figure 2 Genome size and number distribution of jumbo phages.
目前已分离鉴定的巨型噬菌体中大多数以革兰氏阴性菌(Gram-negative)为宿主菌,如假单胞菌(Pseudomonas)和柄杆菌(Caulobacter)等,也有少部分巨型噬菌体的宿主菌为革兰氏阳性菌(Gram-positive),如金黄色葡萄球菌(Staphylococcus aureus)
2 巨型噬菌体的基因组与进化
巨型噬菌体的基因组不仅容量更大,而且在基因排布方式、基因功能的复杂性以及生物学策略的多样性等方面展现出显著特点。深入探究巨型噬菌体的基因组特征,有助于更全面地理解噬菌体这一生命形式的生存机制及进化历程,进而揭示其如何在自然选择中演化出如此庞大的基因组,以及这些额外基因如何赋予它们相较于普通噬菌体更为多样的生存策略和更强的环境适应能力。不同物种基因组中功能基因的组织形式各具特色,原核细菌的功能基因倾向于成簇化排

图3 巨型噬菌体ΦKZ的基因组图谱
Figure 3 Genomic map of the jumbo phage ΦKZ.
巨型噬菌体拥有更大的基因组意味着其拥有数量更多、种类更加多样的基因,从而可赋予其在DNA复制、转录、翻译和核苷酸代谢等多个生命过程中更高的自主性。对多种巨型噬菌体的测序分析发现其基因组中除了必需的早、中、晚期基因外,还包含大量的RNA 聚合酶(RNA polymerase, RNAP)基因、转运RNA (transfer RNA, tRNA)合成酶基因、tRNA修饰酶基因、翻译起始元件、编码延伸因子以及核糖体蛋白等多种功能DNA序
目前对已测序的巨型噬菌体基因组进行的功能注释尚不完善,部分DNA序列的功能尚未明确,还存在大量编码未知功能蛋白的基因。例如,其马利病毒科的典型成员ΦKZ噬菌体基因组中未知蛋白基因约占其基因总数的75
通过全基因组序列比对,构建了宿主为大肠杆菌、铜绿假单胞菌、肺炎克雷伯氏菌等的部分巨型噬菌体的发育树,结果显示拥有相同种属宿主菌且基因组大小相近的巨型噬菌体在发育关系上更为接近(

图4 巨型噬菌体的发育树
Figure 4 Phylogenetic tree of jumbo phages.
3 巨型噬菌体的复制机制及相关特殊结构
与普通噬菌体一样,巨型噬菌体为了成功复制,必须精确调控宿主菌的基因表
随着不同来源的巨型噬菌体被不断分离、鉴定与研究,其丰富多样的生物学特性正逐步被揭示和解析。在目前已发现的巨型噬菌体中,一些特殊的生物学特性引起了广泛关注。首先是巨型噬菌体在复制过程中可在宿主菌内部形成类似“细胞核”的核状区室,这一独特结构对于理解噬菌体在感染细菌过程中的复制机制具有重要意
3.1 巨型噬菌体的核状区室
噬菌体基因组在感染初期易受细菌防御系统的攻击,而某些巨型噬菌体会组装一个基于蛋白质的核状区室来保护复制中的噬菌体DNA。2017年,Joe Pogliano团队在研究噬菌体201Ф2-1感染细菌的过程中,观察到一个核状(nucleus-like)结构的组

图5 成核巨型噬菌体感染宿主细菌过程示意图
Figure 5 Schematic diagram of the infection process of host bacteria by nucleus-forming jumbo phages.
核状区室结构不仅帮助成核巨型噬菌体完成复制,还为噬菌体基因组提供了有效保护,使其免受靶向DNA的细菌防御系统的攻击(

图6 成核巨型噬菌体对宿主防御系统的抵抗机制示意图
Figure 6 Schematic diagram of the resistance mechanisms of nucleus-forming jumbo phages to host defense systems.
以上研究表明,这些核状区室可能最初是作为对抗细菌免疫系统的保护机制而演化出来
3.2 巨型噬菌体复制相关的其他特殊结构
巨型噬菌体在复制过程中,除了可形成核状区室外,还拥有其他起重要作用的特殊结构,如噬菌体内体、长波浪卷曲尾丝和膜囊泡等,它们不仅有助于噬菌体基因组的包装,还参与了宿主菌的识别以及其他关键过
除了内体,巨型噬菌体的另一个特殊结构是在噬菌体0305Ф8-3

图7 噬菌体vB_BpuM_BpSp分离的尾部亚结
Figure 7 Separated tail substructure of phage vB_BpuM_BpS
此外,成核噬菌体在感染宿主菌时还会形成早期噬菌体感染(early phage infection, EPI)囊泡(
4 巨型噬菌体的应用
巨型噬菌体因其宿主谱广、复制周期独特、杀菌活性强等特性,在抗病原菌感染、环境治理、水产养殖和生物防治等多个方面展现出良好的应用前
在环境治理方面,巨型噬菌体同样展现出应用价值。比如,2023年Hu
随着对巨型噬菌体生物学特性的认识逐渐深化,以及噬菌体分离鉴定技术、高通量测序技术和各种组学技术的不断发展和完善,未来有望从医院环境和临床样本中分离出更多具有潜在应用价值的巨型噬菌体,为基础研究和临床抗感染治疗提供更丰富、有良好应用价值的噬菌体资源。
5 总结与展望
近年来,巨型噬菌体的发现与研究日益增多,使我们对其生物学特性及基因组有了更为深入的了解。一些独特的生物学构造,如核状区室、内体和长波浪卷曲尾丝等,在不同巨型噬菌体的复制过程中被发现,极大地丰富了我们对噬菌体生物学多样性的认知。巨型噬菌体的基因组堪称遗传信息的宝库,其中蕴含的丰富基因资源为探索生命科学的奥秘,包括噬菌体多样性、基因组的进化等,提供了更多可能性,展现出巨大的研究潜力。尽管如此,目前仍存在大量未被阐明的巨型噬菌体生物学机制,如噬菌体如何精密调控宿主菌、其反防御系统的运作原理以及基因组中大量未知功能蛋白的分子特性等。未来相关研究将深化我们对巨型噬菌体与宿主菌相互作用的理解,并为开发新型抗菌药物和治疗策略开辟新途径。
噬菌体疗法在解决耐药菌感染方面具有巨大潜力,但仍面临许多挑战,其中之一是细菌对抗噬菌体的防御系
尽管巨型噬菌体在抗病原菌感染等领域已展现出较大潜力,但当前研究仍面临诸多限制和挑战。由于巨型噬菌体的研究起步较晚,已分离的巨型噬菌体种类相对较少,且基因组注释尚不完善,机制解析仍停留在实验室研究阶段。这使得我们对巨型噬菌体的认识仍然有限,无法充分发挥其潜在的应用价值。对于已分离出的巨型噬菌体,其表征尚不全面。大量的DNA序列和假定蛋白编码基因的功能仍然未知,这些编码不明功能的噬菌体蛋白是否存在潜在危害,目前尚无法准确预测。这种不确定性不仅限制了巨型噬菌体在临床应用中的安全性评估,也阻碍了其作为治疗制剂的进一步开发和利用。在技术层面,操纵较常规噬菌体基因组更大的巨型噬菌体基因组仍存在瓶颈,这限制了对巨型噬菌体的利用和改造。目前尚未见关于巨型噬菌体设计改造的报道,但巨型噬菌体的基因组容量较大,其基因组的删减和扩展都具有更大的改造空间。随着技术的深度融合与持续创新,巨型噬菌体基因组改造的瓶颈有望被打破,从而释放出更大的应用潜力。
因此,为了解决当前面临的挑战并充分发挥巨型噬菌体的潜力,需要进一步研究和探索新的技术手段,继续深入研究和解析巨型噬菌体的生物学特性、基因组结构、功能机制及其在抗感染治疗中的应用前景。通过不断完善基因组注释、拓展巨型噬菌体的种类、解析生物学机制和突破技术瓶颈,有望为耐药菌的临床抗感染治疗研制更加有效、安全的噬菌体制剂,推动噬菌体治疗的发展。
作者贡献声明
何博:文章撰写,绘制图5、图6,引用图1、图7;姜昕宇:文章审阅;廖江林:生物信息学统计分析,绘制图3、图4;卢曙光:文章审核与修改,整理相关数据并绘制图2;乐率:综述选题及确定文章主旨和结构,文章修改。
利益冲突
作者声明不存在任何可能会影响本文所报告工作的已知经济利益或个人关系。
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