title: Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus.
abstract: Staphylococcus aureus is a leading infectious cause of life-threatening disease in humans, yet there is currently no vaccine to combat this bacterium. The pathogenesis of S. aureus is mediated by a diverse array of protein toxins including a large family of secreted pyrogenic superantigens. Neutralization of superantigens, including SEB and TSST-1, has proven to be protective in several animal models of toxic shock and sepsis. We demonstrate, for the first time, that a far more prevalent staphylococcal superantigen, SEK, can also induce lethal shock in mice. Additionally, we describe monoclonal antibodies (mAbs) that inhibit SEK-induced mitogenicity as well as protect against SEK-induced lethality, and enhance survival from S. aureus septicemia in murine models. MAb-4G3 (IgG2b), mAb-5G2 (IgG1), and mAb-9H2 (IgG1), all inhibit SEK-induced proliferation and cytokine production of human immune cells. We then demonstrate that passive immunization with a combination of mAb-4G3 and mAb-5G4, 2 mAbs that do not compete for epitope(s) on SEK, significantly enhance survival in a murine model of SEK-induced toxic shock (p = 0.006). In the setting of sepsis, passive immunization with this combination of mAbs also significantly enhances survival in mice after challenge with CA-MRSA strain USA300 (p = 0.03). Furthermore, septic mice that received mAb treatment in conjunction with vancomycin exhibit less morbidity than mice treated with vancomycin alone. Taken together, these findings suggest that the contribution of SEK to S. aureus pathogenesis may be greater than previously appreciated, and that adjunctive therapy with passive immunotherapy against SEs may be beneficial.
authors.affiliation: a Department of Microbiology and Immunology , Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Aguilar
authors.affiliation: a Department of Microbiology and Immunology , Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: Avanish K
authors.initials: AK
authors.lastname: Varshney
authors.affiliation: b Department of Systems and Computational Biology , Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: Ximo
authors.initials: X
authors.lastname: Pechuan
authors.affiliation: c New York Structural Biology Center , New York , NY , USA.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Dutta
authors.affiliation: a Department of Microbiology and Immunology , Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nosanchuk
authors.affiliation: d Department of Molecular Genetics and Microbiology , Stony Brook University , Stony Brook , NY , USA.
authors.forename: Bettina C
authors.initials: BC
authors.lastname: Fries
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000907:Antibodies, Bacterial / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000276:immunology* / Q000633:toxicity*; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D051379:Mice; D012772:Shock, Septic / Q000517:prevention & control*; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control* / Q000628:therapy; D013211:Staphylococcus aureus / Q000276:immunology / Q000472:pathogenicity*; D014640:Vancomycin / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D004768:Enterotoxins; D014640:Vancomycin
keywords: Staphylococcal Enterotoxin B; Staphylococcal Enterotoxin K; toxic shock syndrome toxin 1