Characterization of alpha-toxin hla gene variants, alpha-toxin expression levels, and levels of antibody to alpha-toxin in hemodialysis and postsurgical patients with Staphylococcus aureus bacteremia.
Alpha-toxin is a major Staphylococcus aureus virulence factor. This study evaluated potential relationships between in vitro alpha-toxin expression of S. aureus bloodstream isolates, anti-alpha-toxin antibody in serum of patients with S. aureus bacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwent spa typing and hla sequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encoded hla (197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%). In vitro alpha-toxin levels were inversely associated with survival (cure, 2.19 μg/ml, versus failure, 1.09 μg/ml; P < 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95; P < 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27; P < 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressing S. aureus isolates (P < 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis of hla revealed 12 distinct hla genotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinical S. aureus isolates. Higher in vitro alpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producing S. aureus exhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study.
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA fowle003@mc.duke.edu batu.sharma@duke.edu.
Batu K
BK
Sharma-Kuinkel
MedImmune, LLC, Gaithersburg, Maryland, USA.
Yuling
Y
Wu
MedImmune, LLC, Gaithersburg, Maryland, USA.
David E
DE
Tabor
MedImmune, LLC, Gaithersburg, Maryland, USA.
Hoyin
H
Mok
MedImmune, LLC, Gaithersburg, Maryland, USA.
Bret R
BR
Sellman
MedImmune, LLC, Gaithersburg, Maryland, USA.
Amy
A
Jenkins
MedImmune, LLC, Gaithersburg, Maryland, USA.
Li
L
Yu
MedImmune, LLC, Gaithersburg, Maryland, USA.
Hasan S
HS
Jafri
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Thomas H
TH
Rude
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Felicia
F
Ruffin
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Wiley A
WA
Schell
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Lawrence P
LP
Park
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Qin
Q
Yan
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Joshua T
JT
Thaden
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Julia A
JA
Messina
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Durham, North Carolina, USA fowle003@mc.duke.edu batu.sharma@duke.edu.
Vance G
VG
Fowler
MedImmune, LLC, Gaithersburg, Maryland, USA.
Mark T
MT
Esser
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D016470:Bacteremia; D001427:Bacterial Toxins / Q000235:genetics* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006460:Hemolysin Proteins / Q000235:genetics* / Q000276:immunology; D006461:Hemolysis / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011817:Rabbits; D006435:Renal Dialysis / Q000009:adverse effects; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D017211:Treatment Failure; D016896:Treatment Outcome; D055815:Young Adult
D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin