Stable antibiotic resistance and rapid human adaptation in livestock-associated MRSA.
Stable antibiotic resistance and rapid human adaptation in livestock-associated MRSA.
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DOI：
10.7554/elife.74819
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发表时间：
2022-06-28
期刊：
影响因子：
7.7
通讯作者：
Wilson, Daniel J.
中科院分区：
文献类型：
--
作者：
Matuszewska, Marta;Murray, Gemma G. R.;Ba, Xiaoliang;Wood, Rhiannon;Holmes, Mark A.;Weinert, Lucy A.;Wilson, Daniel J.
移动遗传元件（MGEs）是细菌中水平基因转移的媒介，但也可以由子细胞垂直遗传。建立导致细菌基因组中MGEs当代模式的动力学对于预测新型和耐药病原体的出现和进化至关重要。耐甲氧西林金黄色葡萄球菌（MRSA）克隆复合物（CC） 398是欧洲家畜中主要的MRSA，也是人类感染的一个日益增长的原因。先前的研究已经确定了三类MGEs，它们的存在或不存在将家畜相关的CC398与密切相关且抗生素耐药性较低的人类相关种群区分开来。在这里，我们利用从牲畜和人类中采集的1180个CC398基因组，在27年的时间里，充分表征了这些MGEs的进化动态。我们发现家畜相关CC398的出现与携带四环素抗性基因的Tn916转座子的获得同时发生，该基因已经稳定遗传了57年。随后获得了携带甲氧西林、四环素和重金属耐药基因的V型SCCmec，该基因维持了35年，偶尔被截断和替换为IV型SCCmec。相比之下，一类携带人类免疫逃避基因簇的噬菌体，在牲畜相关的CC398中基本缺失，在人类和牲畜相关的CC398中反复获得和丢失。这些对比动态意味着，当家畜相关的MRSA传播给人类时，对人类宿主的适应超过了抗生素耐药性的丧失。此外，与耐药性相关的MGEs的稳定遗传表明，欧洲农场持续减少抗生素和氧化锌的使用对与牲畜相关的MRSA的影响将缓慢实现。耐抗生素感染对人类健康的威胁日益严重。2019年，这些难以治疗的感染导致495万人死亡，使其成为当年的第三大死因。人类过度使用抗生素可能会导致耐药细菌的出现。但人们担心，在牲畜养殖场使用抗生素也是原因之一。在欧洲，一种可以追溯到牲畜的细菌越来越多地导致人类感染，而这些感染对抗生素甲氧西林治疗无效。它被称为家畜相关的耐甲氧西林金黄色葡萄球菌（LA-MRSA）。细菌可以共享使它们具有抗药性或更致命的基因。这些基因通常携带在可移动的遗传元件上，促进它们从一个细菌细胞移动到另一个细菌细胞。在欧洲，LA-MRSA最常见的类型是克隆复合物398 （CC398）。它有两个携带抗生素抗性基因的可移动遗传元素，但通常缺乏帮助细菌逃脱人体免疫系统的可移动遗传元素。了解更多关于LA-MRSA如何获得这些基因变化的信息可能有助于科学家制定更好的策略来保护公众。Matuszewska、Murray等人分析了27年来从28个国家的人类、猪和其他13种动物身上收集的1000多个CC398样本的基因组。他们利用这些数据重建了细菌的进化史。Matuszewska、Murray等人表明，CC398中含有抗生素耐药基因的两个可移动元件是在几十年前获得的。其中一个超过50岁，可能是在抗生素在牲畜中使用变得普遍的时候获得的。虽然牲畜中的大多数CC398没有帮助LA-MRSA逃避人类免疫系统的移动元件，但它们在感染人类时经常获得它。这导致高度耐药的人类MRSA感染。本研究结果提示，LA-MRSA对人类健康构成严重威胁。这种细菌的抗药性已经持续了几十年，在不同的牲畜品种和不同的国家传播。牲畜中的这些耐药细菌很容易感染人类。目前减少农场抗生素使用的努力可能需要几十年才能减轻这些风险。此外，欧盟禁止牲畜使用氧化锌的禁令（将于2022年6月生效）可能无助于减少LA-MRSA，因为赋予细菌抗性的基因与锌处理并不总是相关的。
Mobile genetic elements (MGEs) are agents of horizontal gene transfer in bacteria, but can also be vertically inherited by daughter cells. Establishing the dynamics that led to contemporary patterns of MGEs in bacterial genomes is central to predicting the emergence and evolution of novel and resistant pathogens. Methicillin-resistant Staphylococcus aureus (MRSA) clonal-complex (CC) 398 is the dominant MRSA in European livestock and a growing cause of human infections. Previous studies have identified three categories of MGEs whose presence or absence distinguishes livestock-associated CC398 from a closely related and less antibiotic-resistant human-associated population. Here, we fully characterise the evolutionary dynamics of these MGEs using a collection of 1180 CC398 genomes, sampled from livestock and humans, over 27 years. We find that the emergence of livestock-associated CC398 coincided with the acquisition of a Tn916 transposon carrying a tetracycline resistance gene, which has been stably inherited for 57 years. This was followed by the acquisition of a type V SCCmec that carries methicillin, tetracycline, and heavy metal resistance genes, which has been maintained for 35 years, with occasional truncations and replacements with type IV SCCmec. In contrast, a class of prophages that carry a human immune evasion gene cluster and that are largely absent from livestock-associated CC398 have been repeatedly gained and lost in both human- and livestock-associated CC398. These contrasting dynamics mean that when livestock-associated MRSA is transmitted to humans, adaptation to the human host outpaces loss of antibiotic resistance. In addition, the stable inheritance of resistance-associated MGEs suggests that the impact of ongoing reductions in antibiotic and zinc oxide use in European farms on livestock-associated MRSA will be slow to be realised. Antibiotic-resistant infections are a growing threat to human health. In 2019, these hard-to-treat infections resulted in 4.95 million deaths making them the third leading cause of death that year. Excessive use of antibiotics in humans is likely driving the emergence of drug-resistant bacteria. But there is a concern that use of antibiotics on livestock farms is also contributing. A type of bacteria traced back to livestock is a growing cause of human infections that do not respond to treatment with the antibiotic methicillin in Europe. It is called livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA). Bacteria can share genes that make them drug resistant or more deadly. These genes are often carried on mobile genetic elements that promote their movement from one bacterial cell to another. The most common type of LA-MRSA in Europe is clonal-complex 398 (CC398). It has two mobile genetic elements carrying antibiotic-resistance genes, but generally lacks a mobile genetic element that helps the bacterium escape the human immune system. Learning more about how LA-MRSA acquired these genetic changes may help scientists develop better strategies to protect the public. Matuszewska, Murray et al. analyzed the genomes of more than 1,000 samples of CC398 collected from humans, pigs and 13 other animal species in 28 countries over 27 years. They used this data to reconstruct the bacteria’s evolutionary history. Matuszewska, Murray et al. show that two mobile elements containing antibiotic resistance genes in CC398 were gained decades ago. One is more than 50 years old and was likely acquired around the time antibiotic use in livestock became common. While most CC398 in livestock do not have a mobile element that helps LA-MRSA evade the human immune system, they often gain it when they infect humans. This leads to highly drug-resistant human MRSA infections. The results of this study suggest that LA-MRSA is a serious threat to human health. The resistance of this bacterium has persisted for decades, spreading across different livestock species and different countries. These drug-resistant bacteria in livestock readily infect humans. Current efforts to reduce antibiotic use in farms may take decades to mitigate these risks. Additionally, the ban on zinc-oxide use on livestock in the European Union (coming into force June 2022) may not help reduce LA-MRSA, because the genes conferring resistance to bacteria and zinc treatment are not always linked.