Department of Veterinary and Animal Sciences, University of Copenhagengrid.5254.6, Copenhagen, Denmark.
Department of Bacteria, Parasites and Fungi, Statens Serum Institutgrid.6203.7, Copenhagen, Denmark.
mBio. 2021 Dec 21;12(6):e0225921. doi: 10.1128/mBio.02259-21. Epub 2021 Dec 7.
Bacterial pathogens commonly carry prophages that express virulence factors, and human strains of Staphylococcus aureus carry Sa3int phages, which promote immune evasion. Recently, however, these phages have been found in livestock-associated, methicillin-resistant S. aureus (LA-MRSA). This is surprising, as LA-MRSA strains contain a mutated primary bacterial integration site, which likely explains why the rare integration events that do occur mostly happen at alternative locations. Using deep sequencing, we show that after initial integration at secondary sites, Sa3int phages adapt through nucleotide changes in their attachment sequences to increase homology with alternative bacterial attachment sites. Importantly, this homology significantly enhances integrations in new rounds of infections. We propose that promiscuity of the phage-encoded tyrosine recombinase is responsible for establishment of Sa3int phages in LA-MRSA. Our results demonstrate that phages can adopt extensive population heterogeneity, leading to establishment in strains lacking bona fide integration sites. Ultimately, their presence may increase virulence and zoonotic potential of pathogens with major implications for human health. A growing number of humans are being infected by antibiotic resistant Staphylococcus aureus originating from livestock. The preference of S. aureus for humans or animals is in part determined by factors encoded by viruses (phages) that reside in the bacterial genome. Here, we reveal a process by which phages adapt to and become integrated in new strains of S. aureus lacking the preferred phage integration site. We propose that this is due to the relaxed specificity of a phage-encoded enzyme called recombinase. As this recombinase is used by many other phages, our results might have implications for a broader range of phages. Importantly, the adaptation described here enables S. aureus to jump between host organisms and increases its zoonotic threat.
细菌病原体通常携带表达毒力因子的噬菌体，而金黄色葡萄球菌的人类菌株携带 Sa3int 噬菌体，促进免疫逃避。然而，最近这些噬菌体已在与牲畜相关的耐甲氧西林金黄色葡萄球菌 (LA-MRSA) 中发现。这很令人惊讶，因为 LA-MRSA 菌株含有突变的主要细菌整合位点，这可能解释了为什么罕见的整合事件主要发生在替代位置。使用深度测序，我们表明 Sa3int 噬菌体在最初整合到次要位置后，通过其附着序列中的核苷酸变化进行适应，以增加与替代细菌附着位点的同源性。重要的是，这种同源性显著增强了新轮感染中的整合。我们提出噬菌体编码的酪氨酸重组酶的混杂性是 Sa3int 噬菌体在 LA-MRSA 中建立的原因。我们的结果表明，噬菌体可以采用广泛的种群异质性，导致在缺乏真正整合位点的菌株中建立。最终，它们的存在可能会增加缺乏真正整合位点的病原体的毒力和人畜共患潜力，对人类健康产生重大影响。越来越多的人类感染源自牲畜的抗生素耐药金黄色葡萄球菌。金黄色葡萄球菌对人类或动物的偏好部分取决于存在于细菌基因组中的病毒（噬菌体）编码的因素。在这里，我们揭示了一种噬菌体适应和整合缺乏首选噬菌体整合位点的新金黄色葡萄球菌菌株的过程。我们提出，这是由于噬菌体编码的一种称为重组酶的酶的特异性放松所致。由于这种重组酶被许多其他噬菌体使用，我们的结果可能对更广泛的噬菌体产生影响。重要的是，这里描述的适应使金黄色葡萄球菌能够在宿主生物之间跳跃，并增加其人畜共患威胁。
