title: Exploiting dominant-negative toxins to combat Staphylococcus aureus pathogenesis.
abstract: Staphylococcus aureus (S. aureus) is a human pathogen that relies on the subversion of host phagocytes to support its pathogenic lifestyle. S. aureus strains can produce up to five beta-barrel, bi-component, pore-forming leukocidins that target and kill host phagocytes. Thus, preventing immune cell killing by these toxins is likely to boost host immunity. Here, we describe the identification of glycine-rich motifs within the membrane-penetrating stem domains of the leukocidin subunits that are critical for killing primary human neutrophils. Remarkably, leukocidins lacking these glycine-rich motifs exhibit dominant-negative inhibitory effects toward their wild-type toxin counterparts as well as other leukocidins. Biochemical and cellular assays revealed that these dominant-negative toxins work by forming mixed complexes that are impaired in pore formation. The dominant-negative leukocidins inhibited S. aureus cytotoxicity toward primary human neutrophils, protected mice from lethal challenge by wild-type leukocidin, and reduced bacterial burden in a murine model of bloodstream infection. Thus, we describe the first example of staphylococcal bi-component dominant-negative toxins and their potential as novel therapeutics to combat S. aureus infection.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Reyes-Robles
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Ashira
authors.initials: A
authors.lastname: Lubkin
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Alonzo
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: D Borden
authors.initials: DB
authors.lastname: Lacy
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA victor.torres@nyumc.org.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Torres
mesh_terms: D000818:Animals; D003603:Cytotoxins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D005998:Glycine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007956:Leukocidins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D009154:Mutation; D009504:Neutrophils / Q000382:microbiology; D010586:Phagocytes / Q000382:microbiology; D000072417:Protein Domains; D055503:Protein Multimerization; D013203:Staphylococcal Infections / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence / Q000235:genetics
chemical_list: D003603:Cytotoxins; D007956:Leukocidins; D005998:Glycine
keywords: Staphylococcus aureus; bi‐component; dominant‐negative; leukocidin; pore‐forming toxin