Passive therapy with humanized anti-staphylococcal enterotoxin B antibodies attenuates systemic inflammatory response and protects from lethal pneumonia caused by staphylococcal enterotoxin B-producingStaphylococcus aureus

Abstract

Drugs such as linezolid that inhibit bacterial protein synthesis may be beneficial in treating infections caused by toxigenic Staphylococcus aureus. As protein synthesis inhibitors have no effect on preformed toxins, neutralization of pathogenic exotoxins with anti-toxin antibodies may be beneficial in conjunction with antibacterial therapy. Herein, we evaluated the efficacy of human-mouse chimeric high-affinity neutralizing anti-staphylococcal enterotoxin B (SEB) antibodies in the treatment of experimental pneumonia caused by SEB-producing S. aureus. Since HLA class II transgenic mice mount a stronger systemic immune response following challenge with SEB and are more susceptible to SEB-induced lethal toxic shock than conventional mice strains, HLA-DR3 transgenic mice were used. Lethal pneumonia caused by SEB-producing S. aureus in HLA-DR3 transgenic mice was characterized by robust T cell activation and elevated systemic levels of several pro-inflammatory cytokines and chemokines. Prophylactic administration of a single dose of linezolid 30 min prior to the onset of infection attenuated the systemic inflammatory response and protected from mortality whereas linezolid administered 60 min after the onset of infection failed to confer significant protection. Human-mouse chimeric high-affinity neutralizing anti-SEB antibodies alone, but not polyclonal human IgG, mitigated this response and protected from death when administered immediately after initiation of infection. Further, anti-SEB antibodies as well as intact polyclonal human IgG, but not its Fab or Fc fragments, protected from lethal pneumonia when followed with linezolid therapy 60 min later. In conclusion, neutralization of superantigens with high-affinity antibodies may have beneficial effects in pneumonia.

“Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor

“…T cells from DR3.GFP transgenic mice rapidly express GFP following TCR-mediated T cell activation ( 37 , 38 ). We have shown previously that even SAgs are capable of upregulating GFP in T cells from DR3.GFP transgenic mice in vivo and in vitro ( 19 ) and ruxolitinib inhibited SAg-driven upregulation of GFP in T cells from DR3.GFP transgenic mice ( Figure 7 ).…”

“…AE°.HLA-DR3 transgenic mice expressing HLA-DRA1 * 0101 and HLA-DRB1 * 0301 transgenes on the complete mouse MHC-II–deficient background (AE°), HLA-DR3.Nur-77 GFP transgenic mice expressing green fluorescent protein (GFP) under the control of Nur-77 promoter and AE°.HLA-DR3.IFN-γ −/− mice are described elsewhere ( 14 , 15 , 17 – 19 ). AE°.HLA-DR3.IL-17A −/− mice were produced by crossing IL-17A-deficient mice obtained from Dr. Yoichiro Iwakura, Tokyo University of Science ( 20 ), with AE°.HLA-DR3 mice for several generations.…”

Antibody-Based Agents in the Management of Antibiotic-Resistant Staphylococcus aureus Diseases

“…Therapeutic treatment with humanized anti-SEB antibodies protected mice in a SEB intoxication model as well as in sepsis and deep-tissue infection models [ 106 ]. Along this line, administration of human-mouse chimeric high-affinity anti-SEB antibodies attenuated the systemic inflammatory response caused by SEB-producing S. aureus and protected from lethal pneumonia [ 107 ]. Likewise, passive administration of a combination of mAb-4G3 and mAb-5G4, two mAbs recognizing different epitopes on staphylococcal enterotoxin K (SEK), significantly enhanced survival of mice in a model of SEK-induced lethal shock and sepsis [ 108 ].…”

Staphylococcus aureustoxin antibodies: Good companions of antibiotics and vaccines

“…The data shown by Karau et al 16 suggest that therapeutic effects of an antibiotic given once a S. aureus infection is established could be ineffective in blocking progression of disease mechanisms driven by secreted toxins such as SEB, Hla and leukocidins already accumulated in the lungs (Fig. 1).…”

“…In this issue Karau and colleagues 16 present a research study which aims at understanding the potential contribution of a passive therapy approach against S. aureus pneumonia using a pair of mAbs, targeting different epitopes of SEB. The antibodies are high-affinity human-mouse chimera and together they show enhanced neutralization of SEB superantigenicity both in vitro and in vivo as shown by the same group in previous publications.…”