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Stable antibiotic resistance and rapid human adaptation in livestock-associated MRSA.

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 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.

SUBMITTER: Matuszewska M

PROVIDER: S-EPMC9239682 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) sequence type 9 (ST9) has emerged and disseminated in Asia. It is associated with colonization or infection in both humans and animal hosts; however, the genetic factors underpinning its adaptation to animal and human population remain to be determined. Here, we conducted a genomic analysis of 191 ST9 S. aureus genomes collected from 12 different countries, including 174 genomes retrieved from public databases and 17 sequenced in this study. In silico spa typing, staphylococcal cassette chromosome mec (SCCmec) typing, and antimicrobial resistance and virulence gene mining were conducted, and the temporal phylogenetic signal was assessed by Bayesian inference. Our results point toward a human methicillin-susceptible S. aureus (MSSA) origin of ST9 that evolved approximately 2 centuries ago. Three major genetic events occurred during ST9 host shift from human to animals: the loss of the immune evasion cluster genes (scn, chp, and sak), which were reported to contribute to virulence in human infections, the acquisition of the SaPIbov4-like element-encoding vwb gene, which is an animal-specific virulence factor responsible for the clotting of animal plasma, and the acquisition of antibiotic resistance genes, including SCCmec, quinolone resistance-determining region (QRDR) mutations, and a multidrug resistance genetic element (MDRST9). Evidence of direct transmission of animal-adapted strains to human hosts also suggest that transmission could potentially reshape the resistance and virulence genetic pool in these isolates. The rapid clonal expansion of MDR ST9 strains in mainland China and Taiwan highlights the increasing need for effective surveillance of antibiotic consumption in animal husbandry to control antimicrobial resistance spread. IMPORTANCE Staphylococcus aureus sequence type 9 (ST9) is the main LA-MRSA clone spreading in the Asian continent. It can colonize and cause mild to severe infections both in animal and humans. Previous work described its genotypic characteristics; however, the molecular history of global spread of ST9 strains remains largely unclear. We conducted a detailed analysis of genomic evolution of global ST9 strains and identified key genetic changes associated with its adaptation to specific hosts. Our results suggest that the ST9 clone originated from human-adapted strains, which lost genes related to the evasion of the immune system. The introduction of ST9 strains in animal populations was aligned with the acquisition of animal-specific virulent factors and mobile elements harboring multiple antimicrobial resistance genes, especially in isolates from mainland China and Taiwan.

Project description:Previous research on methicillin susceptible Staphylococcus aureus (MSSA) belonging to livestock-associated (LA-) sequence type (ST) 398, isolated from pigs and their local surroundings, indicated that differences between these MSSA and their methicillin resistant predecessors (MRSA) are often limited to the absence of the staphylococcal cassette chromosome mec (SCCmec) and few single nucleotide polymorphisms. So far, our understanding on how LA-MRSA endure the environmental conditions associated with pig-farming as well as the putative impact of this particular environment on the mobilisation of SCCmec elements is limited. Thus, we performed in-depth genomic and transcriptomic analyses using the LA-MRSA ST398 strain IMT38951 and its methicillin susceptible descendant. We identified a mosaic-structured SCCmec region including a putative replicative SCCmecVc which is absent from the MSSA chromosome through homologous recombination. Based on our data, such events occur between short repetitive sequences identified within and adjacent to two distinct alleles of the large cassette recombinase genes C (ccrC). We further evaluated the global transcriptomic response of MRSA ST398 to particular pig-farm associated conditions, i.e., contact with host proteins (porcine serum) and a high ammonia concentration. Differential expression of global regulators involved in stress response control were identified, i.e., ammonia-induced alternative sigma factor B-depending activation of genes for the alkaline shock protein 23, the heat shock response and the accessory gene regulator (agr)-controlled transcription of virulence factors. Exposure to serum transiently induced the transcription of distinct virulence factor encoding genes. Transcription of genes reported for mediating the loss of methicillin resistance, especially ccrC, was not significantly different compared to the unchallenged controls. We concluded that, from an evolutionary perspective, bacteria may save energy by incidentally dismissing a fully replicative SCCmec element in contrast to the induction of ccr genes on a population scale. Since the genomic SCCmec integration site is a hot-spot of recombination, occasional losses of elements of 16 kb size may restore capacities for the uptake of foreign genetic material. Subsequent spread of resistance, on the other hand, might depend on the autonomous replication machinery of the deleted SCCmec elements that probably enhance chances for reintegration of SCCmec into susceptible genomes by mere multiplication.

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Stable antibiotic resistance and rapid human adaptation in livestock-associated MRSA.

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