title: Improved Protection in a Rabbit Model of Community-Associated Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia upon Neutralization of Leukocidins in Addition to Alpha-Hemolysin.
abstract: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), especially the USA300 pulsotype, is a frequent cause of skin and soft tissue infections and severe pneumonia. Despite appropriate antibiotic treatment, complications are common and pneumonia is associated with high mortality. S. aureus strains express multiple cytotoxins, including alpha-hemolysin (Hla) and up to five bicomponent leukocidins that specifically target phagocytic cells for lysis. CA-MRSA USA300 strains carry the genes for all six cytotoxins. Species specificity of the leukocidins greatly contributes to the ambiguity regarding their role in S. aureus pathogenesis. We performed a comparative analysis of the leukocidin susceptibility of human, rabbit, and mouse polymorphonuclear leukocytes (PMNs) to assess the translational value of mouse and rabbit S. aureus models. We found that mouse PMNs were largely resistant to LukSF-PV, HlgAB, and HlgCB and susceptible only to LukED, whereas rabbit and human PMNs were highly sensitive to all these cytotoxins. In the rabbit pneumonia model with a USA300 CA-MRSA strain, passive immunization with a previously identified human monoclonal antibody (MAb), Hla-F#5, which cross-neutralizes Hla, LukSF-PV, HlgAB, HlgCB, and LukED, provided full protection, whereas an Hla-specific MAb was only partially protective. In the mouse USA300 CA-MRSA pneumonia model, both types of antibodies demonstrated full protection, suggesting that Hla, but not leukocidin(s), is the principal virulence determinant in mice. As the rabbit recapitulates the high susceptibility to leukocidins characteristic of humans, this species represents a valuable model for assessing novel, cytotoxin-targeting anti-S. aureus therapeutic approaches.
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA binh.diep@ucsf.edu eszter.nagy@arsanis.com.
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Vien T M
authors.initials: VT
authors.lastname: Le
authors.affiliation: Arsanis, Inc./Arsanis Biosciences GmbH, Vienna, Austria.
authors.forename: Zehra C
authors.initials: ZC
authors.lastname: Visram
authors.affiliation: Arsanis, Inc./Arsanis Biosciences GmbH, Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Rouha
authors.affiliation: Arsanis, Inc./Arsanis Biosciences GmbH, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Stulik
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Etyene Castro
authors.initials: EC
authors.lastname: Dip
authors.affiliation: Arsanis, Inc./Arsanis Biosciences GmbH, Vienna, Austria.
authors.forename: Gábor
authors.initials: G
authors.lastname: Nagy
authors.affiliation: Arsanis, Inc./Arsanis Biosciences GmbH, Vienna, Austria binh.diep@ucsf.edu eszter.nagy@arsanis.com.
authors.forename: Eszter
authors.initials: E
authors.lastname: Nagy
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000276:immunology*; D017714:Community-Acquired Infections / Q000382:microbiology; D004195:Disease Models, Animal; D005260:Female; D006460:Hemolysin Proteins / Q000276:immunology*; D006801:Humans; D007956:Leukocidins / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000472:pathogenicity*; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000382:microbiology; D000071067:Pneumonia, Necrotizing / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control*; D011023:Pneumonia, Staphylococcal / Q000276:immunology / Q000517:prevention & control*; D011817:Rabbits
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D007956:Leukocidins; C021091:staphylococcal alpha-toxin