Biomedical subjects

Jodi A Lindsay

Publications and source records attributed to Jodi A Lindsay.

8 recordsLinked to original sources

PubMed2006

Understanding the rise of the superbug: investigation of the evolution and genomic variation of Staphylococcus aureus.

The bacterium Staphylococcus aureus is a common cause of human infection, and it is becoming increasingly virulent and resistant to antibiotics. Our understanding of the evolution of this species has been greatly enhanced by the recent sequencing of the genomes of seven strains of S. aureus. Comparative genomic analysis allows us to identify variation in the chromosomes and understand the mechanisms by which this versatile bacterium has accumulated diversity within its genome structure.

Drug Resistance↗

PubMed2006

Sau1: a novel lineage-specific type I restriction-modification system that blocks horizontal gene transfer into Staphylococcus aureus and between S. aureus isolates of different lineages.

The Sau1 type I restriction-modification system is found on the chromosome of all nine sequenced strains of Staphylococcus aureus and includes a single hsdR (restriction) gene and two copies of hsdM (modification) and hsdS (sequence specificity) genes. The strain S. aureus RN4220 is a vital intermediate for laboratory S. aureus manipulation, as it can accept plasmid DNA from Escherichia coli. We show that it carries a mutation in the sau1hsdR gene and that complementation restored a nontransformable phenotype. Sau1 was also responsible for reduced conjugative transfer from enterococci, a model of vancomycin resistance transfer. This may explain why only four vancomycin-resistant S. aureus strains have been identified despite substantial selective pressure in the clinical setting. Using a multistrain S. aureus microarray, we show that the two copies of sequence specificity genes (sau1hsdS1 and sau1hsdS2) vary substantially between isolates and that the variation corresponds to the 10 dominant S. aureus lineages. Thus, RN4220 complemented with sau1hsdR was resistant to bacteriophage lysis but only if the phage was grown on S. aureus of a different lineage. Similarly, it could be transduced with DNA from its own lineage but not with the phage grown on different S. aureus lineages. Therefore, we propose that Sau1 is the major mechanism for blocking transfer of resistance genes and other mobile genetic elements into S. aureus isolates from other species, as well as for controlling the spread of resistance genes between isolates of different S. aureus lineages. Blocking Sau1 should also allow genetic manipulation of clinical strains of S. aureus.

Bacterial Proteins↗

PubMed2006

Microarrays reveal that each of the ten dominant lineages of Staphylococcus aureus has a unique combination of surface-associated and regulatory genes.

Staphylococcus aureus is the most common cause of hospital-acquired infection. In healthy hosts outside of the health care setting, S. aureus is a frequent colonizer of the human nose but rarely causes severe invasive infection such as bacteremia, endocarditis, or osteomyelitis. To identify genes associated with community-acquired invasive isolates, regions of genomic variability, and the S. aureus population structure, we compared 61 community-acquired invasive isolates of S. aureus and 100 nasal carriage isolates from healthy donors using a microarray spotted with PCR products representing every gene from the seven S. aureus sequencing projects. The core genes common to all strains were identified, and 10 dominant lineages of S. aureus were clearly discriminated. Each lineage carried a unique combination of hundreds of "core variable" (CV) genes scattered throughout the chromosome, suggesting a common ancestor but early evolutionary divergence. Many CV genes are regulators of virulence genes or known or predicted to be expressed on the bacterial surface and to interact with the host during nasal colonization and infection. Within each lineage, isolates showed substantial variation in the carriage of mobile genetic elements and their associated virulence and resistance genes, indicating frequent horizontal transfer. However, we were unable to identify any association between lineage or gene and invasive isolates. We suggest that the S. aureus gene combinations necessary for invasive disease may also be necessary for nasal colonization and that community-acquired invasive disease is strongly dependent on host factors.

Carrier State↗

PubMed2005

Prevalence of methicillin-resistant Staphylococcus aureus among staff and pets in a small animal referral hospital in the UK.

OBJECTIVES: The occurrence of methicillin-resistant Staphylococcus aureus (MRSA) and the possible relatedness between human and animal isolates were investigated among veterinary staff and hospitalized animals in a referral small animal hospital in the UK. METHODS: A total of 300 swab samples were taken from nasal and oral mucosae of 78 veterinary staff, 45 dogs, 12 cats and from 30 environmental surfaces. Staphylococci were isolated by selective enrichment and characterized by biochemical tests and antimicrobial disc susceptibility testing. MRSA isolates were genotypically confirmed by PCR and typed by PFGE. RESULTS: MRSA was isolated from 14 staff (17.9%), four dogs (9%), and three environmental sites (10%) yielding a total of 28 MRSA isolates. PFGE analysis revealed that most MRSA isolates were indistinguishable (56%) or closely related (26%) to EMRSA-15, one of the two epidemic MRSA strains dominant in UK hospitals. Like EMRSA-15, the predominant strain isolated from staff, dogs and environmental sites was resistant to fluoroquinolones in addition to all beta-lactams. CONCLUSIONS: The study provides evidence of EMRSA-15 mucosal carriage in veterinary staff and hospitalized dogs, with the risk of MRSA carriage in veterinary staff being significantly higher than reported for the UK healthy community. EMRSA-15 was predominant in the hospital environment, including humans, dogs, and inanimate objects, but the mode by which the strain was introduced and spread remains uncertain.

Animal Technicians↗

PubMed2005

Design, validation, and application of a seven-strain Staphylococcus aureus PCR product microarray for comparative genomics.

Bacterial comparative genomics has been revolutionized by microarrays, but the power of any microarray is dependent on the number and diversity of gene reporters it contains. Staphylococcus aureus is an important human pathogen causing a wide range of invasive and toxin-mediated diseases, and more than 20% of the genome of any isolate consists of variable genes. Seven whole-genome sequences of S. aureus are available, and we exploited this rare opportunity to design, build, and validate a comprehensive, nonredundant PCR product microarray carrying reporters that represent every predicted open reading frame (3,623 probes). Such a comprehensive microarray necessitated a novel design strategy. Validation with the seven sequenced strains showed correct identification of 93.9% of genes present or absent/divergent but was dependent on the method of analysis chosen. Microarray data were highly reproducible, reducing the need for many replicate slides. Interpretation of microarray data was enhanced by focusing on the major areas of variation--the presence or absence of mobile genetic elements (MGEs). We compiled "composite genomes" of every individual MGE and visualized their distribution. This allowed the sensitive discrimination of related isolates, including the first clear description of how isolates of the same clone of epidemic methicillin-resistant S. aureus differ substantially in their carriage of MGEs. These MGEs carry virulence and resistance genes, suggesting differences in pathogenic potential. The novel methods of design and interpretation of data generated from this microarray will enable further studies of S. aureus evolution, epidemiology, and pathogenesis.

Bacterial Proteins↗

PubMed2004

Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance.

Staphylococcus aureus is an important nosocomial and community-acquired pathogen. Its genetic plasticity has facilitated the evolution of many virulent and drug-resistant strains, presenting a major and constantly changing clinical challenge. We sequenced the approximately 2.8-Mbp genomes of two disease-causing S. aureus strains isolated from distinct clinical settings: a recent hospital-acquired representative of the epidemic methicillin-resistant S. aureus EMRSA-16 clone (MRSA252), a clinically important and globally prevalent lineage; and a representative of an invasive community-acquired methicillin-susceptible S. aureus clone (MSSA476). A comparative-genomics approach was used to explore the mechanisms of evolution of clinically important S. aureus genomes and to identify regions affecting virulence and drug resistance. The genome sequences of MRSA252 and MSSA476 have a well conserved core region but differ markedly in their accessory genetic elements. MRSA252 is the most genetically diverse S. aureus strain sequenced to date: approximately 6% of the genome is novel compared with other published genomes, and it contains several unique genetic elements. MSSA476 is methicillin-susceptible, but it contains a novel Staphylococcal chromosomal cassette (SCC) mec-like element (designated SCC(476)), which is integrated at the same site on the chromosome as SCCmec elements in MRSA strains but encodes a putative fusidic acid resistance protein. The crucial role that accessory elements play in the rapid evolution of S. aureus is clearly illustrated by comparing the MSSA476 genome with that of an extremely closely related MRSA community-acquired strain; the differential distribution of large mobile elements carrying virulence and drug-resistance determinants may be responsible for the clinically important phenotypic differences in these strains.

Drug Resistance, Bacterial↗

PubMed2004

Staphylococcus aureus: superbug, super genome?

Staphylococcus aureus is a common cause of infection in both hospitals and the community, and it is becoming increasingly virulent and resistant to antibiotics. The recent sequencing of seven strains of S. aureus provides unprecedented information about its genome diversity. Subtle differences in core (stable) regions of the genome have been exploited by multi-locus sequence typing (MLST) to understand S. aureus population structure. Dramatic differences in the carriage and spread of accessory genes, including those involved in virulence and resistance, contribute to the emergence of new strains with healthcare implications. Understanding the differences between S. aureus genomes and the controls that govern these changes is helping to improve our knowledge of S. aureus pathogenicity and to predict the evolution of super-superbugs.

Drug Resistance, Bacterial↗

PubMed2001

zur: a Zn(2+)-responsive regulatory element of Staphylococcus aureus.

A putative operon encoding a probable zinc-responsive regulatory element (zur) and components of an ABC-type transporter (mreA mreB) have been characterized in Staphylococcus aureus. The zur gene was inactivated but apparently this did not alter Zn(2+) uptake. Expression of mreAB zur is at a low level under a range of ion conditions. To allow inducible expression of the operon, a construct was made placing it under the control of the IPTG-inducible P(spac) promoter. Using this approach, it was shown that zur is able to repress expression of the entire operon in a Zn(2+)-dependent manner, and that mreA and mreB are likely to be involved in high-affinity ion uptake. zur has no apparent role in pathogenicity in a lesion model of S. aureus infection.

ATP-Binding Cassette Transporters↗