A geographic variant of the Staphylococcus aureus Panton-Valentine leukocidin toxin and the origin of community-associated methicillin-resistant S. aureus USA300.
BACKGROUND
The majority of recent community-associated methicillin-resistant Staphylococcus aureus (MRSA) infections in the United States have been caused by a single clone, USA300. USA300 secretes Panton-Valentine leukocidin (PVL) toxin, which is associated with highly virulent infections.


METHODS
We sequenced the PVL genes of 174 S. aureus isolates from a global clinical sample. We combined phylogenetic reconstruction and protein modeling methods to analyze genetic variation in PVL.


RESULTS
Nucleotide variation was detected at 12 of 1726 sites. Two PVL sequence variants, the R variant and the H variant, were identified on the basis of a substitution at nt 527. Of sequences obtained in the United States, 96.7% harbor the R variant, whereas 95.6% of sequences obtained outside the United States harbor the H variant; 91.3% of MRSA isolates harbor the R variant, and 91.3% of methicillin-susceptible strains harbor the H variant. A molecular model of PVL shows 3 mechanisms by which the amino acid substitution may affect PVL function.


CONCLUSIONS
All sampled PVL genes appear to share a recent common ancestor and spread via a combination of clonal expansion and horizontal transfer. US isolates harbor a variant of PVL that is strongly associated with MRSA infections. Protein modeling reveals that this variant may have functional significance. We propose a hypothesis for the origin of USA300.
O'Hara
F Patrick
FP
Evolutionary and Structural Bioinformatics, Collegeville, Pennsylvania, USA.
Guex
Nicolas
N
Word
J Michael
JM
Miller
Linda A
LA
Becker
Julie A
JA
Walsh
Stacey L
SL
Scangarella
Nicole E
NE
West
Joshua M
JM
Shawar
Ribhi M
RM
Amrine-Madsen
Heather
H
D000328:Adult; D019943:Amino Acid Substitution; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D017714:Community-Acquired Infections / Q000382:microbiology*; D019143:Evolution, Molecular; D005098:Exotoxins / Q000737:chemistry / Q000235:genetics*; D022761:Gene Transfer, Horizontal; D014644:Genetic Variation; D006801:Humans; D007956:Leukocidins / Q000737:chemistry / Q000235:genetics*; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000145:classification* / Q000187:drug effects / Q000235:genetics
D001427:Bacterial Toxins; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; D008712:Methicillin