Stable antibiotic resistance and rapid human adaptation in livestock-associated MRSA
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Evaluation Summary:
Understanding where new strains of microbes come from and how they change over time is important for infection control and prevention. Staphylococcus aureus CC398 is an important strain that 'spills over' from livestock to humans, carrying with it high levels of resistance to antibiotics commonly used in farming. This paper compares more than 1000 genomes of CC398 and concludes that spillover is likely to carry resistance to tetracyclines and other antibiotics into humans that will persist over time.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
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 Tn 916 transposon carrying a tetracycline resistance gene, which has been stably inherited for 57 years. This was followed by the acquisition of a type V SCC mec that carries methicillin, tetracycline, and heavy metal resistance genes, which has been maintained for 35 years, with occasional truncations and replacements with type IV SCC mec . 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.
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Author Response:
Reviewer #2 (Public Review):
The authors sought to reconstruct the evolutionary dynamics of mobile genetic elements (MGEs) in S. aureus using an impressive collection of genomes isolated over more than half a century. Their results confirm that the emergence of the CC398 livestock associated clade coincided with acquisition of the Tn916 transposon, which was then stably maintained. Following this, the CC398 clade acquired methicilin resistance via type V SCCmec, which was largely also maintained, but occasionally lost/truncated or replaced by other SCCmec types. In contrast, human associated pathogenicity genes were repeatedly lost in human-associated and livestock-associated samples. The authors conclude that different dynamics operate for resistance as do pathogenicity genes. The methodology regarding the analysis …
Author Response:
Reviewer #2 (Public Review):
The authors sought to reconstruct the evolutionary dynamics of mobile genetic elements (MGEs) in S. aureus using an impressive collection of genomes isolated over more than half a century. Their results confirm that the emergence of the CC398 livestock associated clade coincided with acquisition of the Tn916 transposon, which was then stably maintained. Following this, the CC398 clade acquired methicilin resistance via type V SCCmec, which was largely also maintained, but occasionally lost/truncated or replaced by other SCCmec types. In contrast, human associated pathogenicity genes were repeatedly lost in human-associated and livestock-associated samples. The authors conclude that different dynamics operate for resistance as do pathogenicity genes. The methodology regarding the analysis of the sequence data looks appropriate. The manuscript could more clearly articulate why finding maintenance of Tn916 is important, for instance, is it expected to impose a fitness cost in the absence of selection for tetracycline resistance? Further, from an evolutionary perspective, the authors could be more convincing about why directly comparing the patterns of acquisition of resistance genes and pathogenicity genes is a desirable thing to do.
We would like to thank the reviewer for their useful comments and criticisms.
We agree with the reviewer that our discussion of our results and their importance could have been made clearer. We have amended our discussion of Tn916 to include more detail about why the maintenance of Tn916 is important and how our observation of its long maintenance within CC398 relates to what is already known about this element.
Previous studies have suggested that Tn916 carriage is associated with a low selective cost in the absence of tetracycline treatment, and this is likely to be part of the explanation of why Tn916 has been maintained by CC398. However, our results more directly relate to the relationship between Tn916 and CC398. They suggest that the element is associated with a selective benefit in CC398, both because it was associated with the origin of CC398 in livestock, and because that the element has been maintained by this lineage for such a long time. While the stability of the element could be promoted by a low selective cost, it is likely that the element would be randomly lost by at least some lineages over such a long time. This is supported by the absence of the element in five livestock-associated CC398 isolates in our collection, and the results of previous studies that have demonstrated experimentally that Tn916 in CC398 is a functional transposon (de Vries et al. 2009; lines 199-201). The widespread maintenance of Tn916, suggests that lineages that lose it are either rapidly outcompeted by those that have maintained it, or they rapidly reacquire it from closely related cells (and never from more distant sources).
We have added a paragraph to our discussion and amended the discussion throughout to make clearer how our results shed light on the dynamics of these elements and why these dynamics matter.
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Evaluation Summary:
Understanding where new strains of microbes come from and how they change over time is important for infection control and prevention. Staphylococcus aureus CC398 is an important strain that 'spills over' from livestock to humans, carrying with it high levels of resistance to antibiotics commonly used in farming. This paper compares more than 1000 genomes of CC398 and concludes that spillover is likely to carry resistance to tetracyclines and other antibiotics into humans that will persist over time.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Staphylococcus aureus is an important bacterial pathogen of humans. Strain CC398 is unusual because it is associated with both humans and livestock. Human infections can originate from livestock, leading to concerns over 'spillover' of antibiotic resistance, which is common CC398. This study aimed to assess the severity of these concerns by investigating the genomes of a large collection of over 1000 CC398. They focused on antibiotic resistance genes and human immune evasion genes that tend to be inherited together and can be spread 'horizontally' between bacteria via 'mobile genetic elements' (MGEs). They found that different MGEs behaved quite differently, and this has implications for spillover. Some tetracyline resistance genes are highly stable and have been maintained since the origin of the …
Reviewer #1 (Public Review):
Staphylococcus aureus is an important bacterial pathogen of humans. Strain CC398 is unusual because it is associated with both humans and livestock. Human infections can originate from livestock, leading to concerns over 'spillover' of antibiotic resistance, which is common CC398. This study aimed to assess the severity of these concerns by investigating the genomes of a large collection of over 1000 CC398. They focused on antibiotic resistance genes and human immune evasion genes that tend to be inherited together and can be spread 'horizontally' between bacteria via 'mobile genetic elements' (MGEs). They found that different MGEs behaved quite differently, and this has implications for spillover. Some tetracyline resistance genes are highly stable and have been maintained since the origin of the livestock-associated CC398s about 60 years ago. This may be relevant because of the use of tetracyclines in farming. Other antibiotic resistance genes are less stable, having been acquired about 35 years ago. Human immune evasion genes come and go much more rapidly. The authors conclude that the stability of antibiotic resistance genes, compared to human immune evasion genes, means that when spillover occurs, antibiotic resistance is likely to be carried with it, and may not be lost quickly even in the absence of farming-associated antibiotics.
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Reviewer #2 (Public Review):
The authors sought to reconstruct the evolutionary dynamics of mobile genetic elements (MGEs) in S. aureus using an impressive collection of genomes isolated over more than half a century. Their results confirm that the emergence of the CC398 livestock associated clade coincided with acquisition of the Tn916 transposon, which was then stably maintained. Following this, the CC398 clade acquired methicilin resistance via type V SCCmec, which was largely also maintained, but occasionally lost/truncated or replaced by other SCCmec types. In contrast, human associated pathogenicity genes were repeatedly lost in human-associated and livestock-associated samples. The authors conclude that different dynamics operate for resistance as do pathogenicity genes. The methodology regarding the analysis of the sequence data …
Reviewer #2 (Public Review):
The authors sought to reconstruct the evolutionary dynamics of mobile genetic elements (MGEs) in S. aureus using an impressive collection of genomes isolated over more than half a century. Their results confirm that the emergence of the CC398 livestock associated clade coincided with acquisition of the Tn916 transposon, which was then stably maintained. Following this, the CC398 clade acquired methicilin resistance via type V SCCmec, which was largely also maintained, but occasionally lost/truncated or replaced by other SCCmec types. In contrast, human associated pathogenicity genes were repeatedly lost in human-associated and livestock-associated samples. The authors conclude that different dynamics operate for resistance as do pathogenicity genes. The methodology regarding the analysis of the sequence data looks appropriate. The manuscript could more clearly articulate why finding maintenance of Tn916 is important, for instance, is it expected to impose a fitness cost in the absence of selection for tetracycline resistance? Further, from an evolutionary perspective, the authors could be more convincing about why directly comparing the patterns of acquisition of resistance genes and pathogenicity genes is a desirable thing to do.
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Reviewer #3 (Public Review):
Matuszewska and colleagues aimed to describe the dynamics of mobile genetic elements in the S. aureus lineage CC398, which is split into a livestock-associated and a human-associated clade. They reconstruct the evolutionary history of this lineage and date several key events in the transition from the human to livestock hosts. Thereby, they are able to re-confirm several previous findings and add relevant knowledge about the dynamics of mobile genetic elements which were crucial in this host transition. They conclude that antimicrobial resistance genes may be maintained in the lineage longer than the lineage requires to acquire certain virulence genes leading to human adaptation.
The authors use a comprehensive collection of publicly available whole-genome sequencing data for this lineage of S. aureus and …
Reviewer #3 (Public Review):
Matuszewska and colleagues aimed to describe the dynamics of mobile genetic elements in the S. aureus lineage CC398, which is split into a livestock-associated and a human-associated clade. They reconstruct the evolutionary history of this lineage and date several key events in the transition from the human to livestock hosts. Thereby, they are able to re-confirm several previous findings and add relevant knowledge about the dynamics of mobile genetic elements which were crucial in this host transition. They conclude that antimicrobial resistance genes may be maintained in the lineage longer than the lineage requires to acquire certain virulence genes leading to human adaptation.
The authors use a comprehensive collection of publicly available whole-genome sequencing data for this lineage of S. aureus and use state of the art analysis to investigate its population structure and the dynamics of mobile genetic elements within the lineage. These analyses have not previously been performed on such an extensive dataset and in this completeness. The results are in good agreement with previous findings and support their conclusions well. The stated aims are achieved.
The article is well structured, well written and the results are summarised in clear high quality figures, which makes the complex results easily available to the reader. A major drawback of the study is, however, the fact that most of the obtained results are a confirmation of previous knowledge. Hence, the contribution to the field is in providing a comprehensive overview of this knowledge, together with the dating of some of the key events in the evolutionary history of this lineage.
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