A multi drug resistant Salmonella enterica 4,[5],12:i- of sequence type 34 (monophasic S . Typhimurium ST34) is a current pandemic clone associated with livestock, particularly pigs, and numerous outbreaks in the human population. A large genomic island, termed SGI-4, is present in the monophasic Typhimurium ST34 clade and absent from other S . Typhimurium strains. SGI-4 consists of 87 open reading frames including sil and pco genes previously implicated in resistance to copper (Cu) and silver, and multiple genes predicted to be involved in mobilization and transfer by conjugation. SGI-4 was excised from the chromosome, circularized, and transferred to recipient strains of S . Typhimurium at a frequency influenced by stress induced by mitomycin C, and oxygen tension. The presence of SGI-4 was associated with increased resistance to Cu, particularly but not exclusively under anaerobic conditions. The presence of silCBA genes, predicted to encode an RND family efflux pump that transports Cu from the periplasm to the external milieu, was sufficient to impart the observed enhanced resistance to Cu, above that commonly associated with S . Typhimurium isolates. The presence of these genes resulted in the absence of Cu-dependent induction of pco genes encoding multiple proteins linked to Cu resistance, also present on SGI-4, suggesting that the system effectively limits the Cu availability in the periplasm, but did not affect SodCI-dependent macrophage survival.
Epidemic and pandemic clones of bacterial pathogens with distinct characteristics continually emerge, replacing those previously dominant through mechanisms that remain poorly characterized. Here, whole-genome-sequencing-powered epidemiology linked horizontal transfer of a virulence gene, sopE, to the emergence and clonal expansion of a new epidemic Salmonella enterica serovar Typhimurium (S. Typhimurium) clone. The sopE gene is sporadically distributed within the genus Salmonella and rare in S . enterica Typhimurium lineages, but was acquired multiple times during clonal expansion of the currently dominant pandemic monophasic S. Typhimurium sequence type (ST) 34 clone. Ancestral state reconstruction and time-scaled phylogenetic analysis indicated that sopE was not present in the common ancestor of the epidemic clade, but later acquisition resulted in increased clonal expansion of sopE-containing clones that was temporally associated with emergence of the epidemic, consistent with increased fitness. The sopE gene was mainly associated with a temperate bacteriophage mTmV, but recombination with other bacteriophage and apparent horizontal gene transfer of the sopE gene cassette resulted in distribution among at least four mobile genetic elements within the monophasic S . enterica Typhimurium ST34 epidemic clade. The mTmV prophage lysogenic transfer to other S. enterica serovars in vitro was limited, but included the common pig-associated S . enterica Derby (S. Derby). This may explain mTmV in S. Derby co-circulating on farms with monophasic S. Typhimurium ST34, highlighting the potential for further transfer of the sopE virulence gene in nature. We conclude that whole-genome epidemiology pinpoints potential drivers of evolutionary and epidemiological dynamics during pathogen emergence, and identifies targets for subsequent research in epidemiology and bacterial pathogenesis.
A multi drug resistant (MDR) Salmonella enterica 4, [5],12:i-of sequence type 34 (monophasic S. Typhimurium ST34) is a current pandemic clone associated with livestock and numerous outbreaks in the human population. A large genomic island, termed SGI-4, is present in the monophasic Typhimurium ST34 clade and absent from other S. Typhimurium strains. SGI-4 consists of 78 open reading frames including sil and pco genes previously implicated in resistance to copper and silver, and multiple genes predicted to be involved in mobilisation and transfer by conjugation. SGI-4 was excised from the chromosome, circularised and transferred to recipient strains of S. Typhimurium at a frequency influenced by stress and induced by mitomycin C and oxygen tension. The presence of SGI-4 was associated with increased resistance to copper, particularly but not exclusively under anaerobic conditions. The presence of silCBA genes, predicted to encode an RND family efflux pump that transports copper from the periplasm to the external milieu, was sufficient to impart the observed enhanced resistance to copper. The presence of silCBA genes resulted in the absence of copper-dependent induction of a multicopper oxidase system encoded by pco genes, also present on SGI-4, suggesting that the system effectively limits the copper availability in the periplasm. The presence of silCBA genes did not affect SodCI-dependent macrophage survival.
Microbial genomes are highly adaptable, with mobile genetic elements (MGEs) such as integrative conjugative elements (ICEs) mediating the dissemination of new genetic information throughout bacterial populations. This is countered by defence mechanisms such as CRISPR-Cas systems, which limit invading MGEs by sequence-specific targeting. Here we report the distribution of the pVir, pTet and PCC42 plasmids and a new 70–129 kb ICE (CampyICE1) in the foodborne bacterial pathogens Campylobacter jejuni and Campylobacter coli . CampyICE1 contains a degenerated Type II-C CRISPR system consisting of a sole Cas9 protein, which is distinct from the previously described Cas9 proteins from C. jejuni and C. coli . CampyICE1 is conserved in structure and gene order, containing blocks of genes predicted to be involved in recombination, regulation and conjugation. CampyICE1 was detected in 134/5829 (2.3 %) C . jejuni genomes and 92/1347 (6.8 %) C . coli genomes. Similar ICEs were detected in a number of non-jejuni/coli Campylobacter species, although these lacked a CRISPR-Cas system. CampyICE1 carries three separate short CRISPR spacer arrays containing a combination of 108 unique spacers and 16 spacer-variant families. A total of 69 spacers and 10 spacer-variant families (63.7 %) were predicted to target Campylobacter plasmids. The presence of a functional CampyICE1 Cas9 protein and matching anti-plasmid spacers was associated with the absence of the pVir, pTet and pCC42 plasmids (188/214 genomes, 87.9 %), suggesting that the CampyICE1-encoded CRISPR-Cas has contributed to the exclusion of competing plasmids. In conclusion, the characteristics of the CRISPR-Cas9 system on CampyICE1 suggests a history of plasmid warfare in Campylobacter .
Microbial genomes are highly adaptable, with mobile genetic elements such as integrative conjugative elements (ICE) mediating the dissemination of new genetic information throughout bacterial populations. This is countered by defence mechanism such as CRISPR-Cas systems, which limit invading mobile elements by targetting specific sequences on these elements. Here we have studied the distribution the pVir, pTet and PCC42 plasmids and a new 70-129 kb ICE (CampyICE1) in the foodborne microbial pathogens Campylobacter jejuni and Campylobacter coli. CampyICE1 contains a degenerated Type II-C CRISPR system consisting of a sole Cas9 protein, which is distinct from the previously described Cas9 proteins from C. jejuni andC. coli. CampyICE1 is highly conserved in structure and gene order, containing blocks of genes predicted to be involved in recombination, regulation and conjugation. CampyICE1 was detected in 134/5,829 (2.3%) C. jejunigenomes and 92/1,347 (6.8%) C. coligenomes. Similar ICE were detected in a number ofnon-jejuni/coli Campylobacter species, which lacked a CRISPR-Cas system. Finally, CampyICE1 contained 3 separate short CRISPR spacer arrays, and a total of 124 unique spacers were identified, of which 67 are predicted to target the Campylobacterplasmids pVir, pTet, and pCC42, and 12 predicted to target other Campylobacter plasmids (63.7%). The presence of a functional CampyICE1 Cas9 protein and matching anti-plasmid spacers was associated with the absence of these plasmids (186/214 genomes), implicating that the CampyICE1-encoded CRISPR-Cas has contributed the exclusion of competing plasmids. Hence the CampyICE1 CRISPR-Cas system may be a part of ongoing plasmid warfare in Campylobacter spp.
Salmonella enterica serovar Typhimurium (S. Typhimurium) comprises a group of closely related human and animal pathogens that account for a large proportion of all Salmonella infections globally. The epidemiological record of S. Typhimurium in Europe is characterized by successive waves of dominant clones, each prevailing for approximately 10–15 years before replacement. Succession of epidemic clones may represent a moving target for interventions aimed at controlling the spread and impact of this pathogen on human and animal health. Here, we investigate the relationship of phage sensitivity and population structure of S. Typhimurium using data from the Anderson phage typing scheme. We observed greater resistance to phage predation of epidemic clones circulating in livestock over the past decades compared to variants with a restricted host range implicating increased resistance to phage in the emergence of epidemic clones of particular importance to human health. Emergence of monophasic S. Typhimurium ST34, the most recent dominant multidrug-resistant clone, was accompanied by increased resistance to phage predation during clonal expansion, in part by the acquisition of the mTmII prophage that may have contributed to the fitness of the strains that replaced ancestors lacking this prophage.
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