中文摘要：金黄色葡萄球菌是一种病原体，可致人从皮肤感染到脓毒性休克的严重疾病。噬菌体是金黄色葡萄球菌的天然杀手，可用于治疗这种细菌感染，也是该菌水平基因转移(HGT)的重要载体。本文使用高通量方法来了解噬菌体敏感细菌株间变异的遗传基础，它决定了噬菌体宿主的范围。筛选259株金黄色葡萄球菌菌株，它们涵盖40多个序列类型，对8种噬菌体敏感，这些噬菌体代表了感染该物种的3种类型。噬菌体的宿主范围变化较大，每种噬菌体能感染73 – 257种细菌。本研究采用全基因组关联分析，确定了可能影响宿主范围的基因座，并通过USA300转座子敲除验证了它们的功能。除了再次发现已知的宿主范围决定因素外，还发现了一些之前未报道的在噬菌体感染期间影响细菌生长的基因，包括trpA、phoR、isdB、sodM、fmtC和relA。使用宿主范围矩阵数据建立了预测模型，准确率达40%-95%。可见金黄色葡萄球菌噬菌体易感性的遗传基础很复杂，但也有了更多资料去了解各种变异。有了宿主范围确定因素的知识，就可以合理设计针对金黄色葡萄球菌宿主范围最广泛的噬菌体治疗混合物，并解决关于噬菌体-宿主相互作用的基本问题，如噬菌体如何影响金黄色葡萄球菌进化。
重点：金黄色葡萄球菌是一种广泛的、医院和社区获得性病原体,许多菌株都耐抗生素。它会导致多种疾病感染，从局部到全身，从皮肤到许多内部器官，包括心脏、肺、骨骼和大脑。它的普遍性、抗生素耐药性和疾病负担使新疗法变得迫切。可以使用噬菌体替代抗生素进行治疗，即使用针对感染细菌的特异性病毒来消除感染。本研究通过测试代表金黄色葡萄球菌物种多样性的菌株的噬菌体宿主范围，并将菌株的基因组序列与宿主范围相联系，鉴定并验证了影响噬菌体宿主范围，即噬菌体感染并杀死菌株的数量的金黄色葡萄球菌基因。这些发现共同提高了我们对噬菌体治疗如何在细菌中起作用的理解，并能更好地预测基于预测感染菌株宿主范围的噬菌体治疗疗效。
外文摘要：Staphylococcus aureus is a human pathogen that causes serious diseases, ranging from skin infections to septic shock. Bacteriophages (phages) are both natural killers of S. aureus, offering therapeutic possibilities, and important vectors of horizontal gene transfer (HGT) in the species. Here, we used high-throughput approaches to understand the genetic basis of strain-to-strain variation in sensitivity to phages, which defines the host range. We screened 259 diverse S. aureus strains covering more than 40 sequence types for sensitivity to eight phages, which were representatives of the three phage classes that infect the species. The phages were variable in host range, each infecting between 73 and 257 strains. Using genome-wide association approaches, we identified putative loci that affect host range and validated their function using USA300 transposon knockouts. In addition to rediscovering known host range determinants, we found several previously unreported genes affecting bacterial growth during phage infection, including trpA, phoR, isdB, sodM, fmtC, and relA. We used the data from our host range matrix to develop predictive models that achieved between 40% and 95% accuracy. This work illustrates the complexity of the genetic basis for phage susceptibility in S. aureus but also shows that with more data, we may be able to understand much of the variation. With a knowledge of host range determination, we can rationally design phage therapy cocktails that target the broadest host range of S. aureus strains and address basic questions regarding phage-host interactions, such as the impact of phage on S. aureus evolution.
  IMPORTANCE Staphylococcus aureus is a widespread, hospital- and community-acquired pathogen, many strains of which are antibiotic resistant. It causes diverse diseases, ranging from local to systemic infection, and affects both the skin and many internal organs, including the heart, lungs, bones, and brain. Its ubiquity, antibiotic resistance, and disease burden make new therapies urgent. One alternative therapy to antibiotics is phage therapy, in which viruses specific to infecting bacteria clear infection. In this work, we identified and validated S. aureus genes that influence phage host range-the number of strains a phage can infect and kill-by testing strains representative of the diversity of the S. aureus species for phage host range and associating the genome sequences of strains with host range. These findings together improved our understanding of how phage therapy works in the bacterium and improve prediction of phage therapy efficacy based on the predicted host range of the infecting strain.
外文关键词：Staphylococcus aureus；bacteriophage lysis；bacteriophage therapy； Bacteriophages；bioinformatics；computational biology；efficiency of plating；evolution；GWAS；phage host range；phage resistance；spot assay
作者：Moller, AG；Winston, K；Ji, SY；Wang, JT；Davis, MNH；Solis-Lemus, CR；Read, TD
作者单位：Emory Univ；Emory Coll Arts & Sc；Univ Wisconsin
期刊名称：MSPHERE
期刊影响因子：4.282
出版年份：2021
出版刊次：1
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