Abstract
Staphylococcus aureus infections lead to an array of illnesses ranging from mild skin infections to serious diseases, such endocarditis, osteomyelitis, and pneumonia. Alpha-toxin (Hla) is a pore-forming toxin, encoded by the hla gene, that is thought to play a key role in S. aureus pathogenesis. A monoclonal antibody targeting Hla, MEDI4893, is in clinical development for the prevention of S. aureus ventilator-associated pneumonia (VAP). The presence of the hla gene and Hla protein in 994 respiratory isolates collected from patients in 34 countries in Asia, Europe, the United States, Latin America, the Middle East, Africa, and Australia was determined. Hla levels were correlated with the geographic location, age of the subject, and length of stay in the hospital. hla gene sequence analysis was performed, and mutations were mapped to the Hla crystal structure. S. aureus supernatants containing Hla variants were tested for susceptibility or resistance to MEDI4893. The hla gene was present and Hla was expressed in 99.0% and 83.2% of the isolates, respectively, regardless of geographic region, hospital locale, or age of the subject. More methicillin-susceptible than methicillin-resistant isolates expressed Hla (86.9% versus 78.8%; P = 0.0007), and S. aureus isolates from pediatric patients expressed the largest amounts of Hla. Fifty-seven different Hla subtypes were identified, and 91% of the isolates encoded an Hla subtype that was neutralized by MED4893. This study demonstrates that Hla is conserved in diverse S. aureus isolates from around the world and is an attractive target for prophylactic monoclonal antibody (MAb) or vaccine development.
Highlights
Staphylococcus aureus infections lead to an array of illnesses ranging from mild skin infections to serious diseases, such endocarditis, osteomyelitis, and pneumonia
To better understand the prevalence of Hla, we characterized the presence of the hla gene, Hla mutations, expression levels, and the relative susceptibility to MEDI4893 in methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) isolates collected as part of an international surveillance program
To better understand the global prevalence of the hla gene and Hla expression in S. aureus respiratory isolates, we randomly selected 500 MSSA and 500 MRSA isolates from a total of 2,068 MSSA and 3,434 MRSA isolates collected during 2012 and 2013 as part of a prospective 5-year global antibacterial resistance surveillance program
Summary
Staphylococcus aureus infections lead to an array of illnesses ranging from mild skin infections to serious diseases, such endocarditis, osteomyelitis, and pneumonia. A monoclonal antibody targeting Hla, MEDI4893, is in clinical development for the prevention of S. aureus ventilator-associated pneumonia (VAP). S. aureus secretes a number of virulence factors to evade the host immune response and contribute to pathogenesis They include superantigens, leukocidins, complement evasion proteins, and the cytolytic toxin Hla [7,8,9]. Active and passive immunization approaches have been effective in preventing skin and soft tissue infections, pneumonia, and death in animal models of S. aureus disease [19,20,21], and epidemiological studies have reported that high levels of anti-Hla serum antibodies correlate with protection from infection or severe disease [22,23,24]. The study was designed to analyze 500 MSSA and 500 MRSA respiratory isolates collected from hospitals in Asia, Europe, the United States, Latin America, the Middle East, Africa, and Australia
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