Chimeric Anti-Staphylococcal enterotoxin B antibodies and lovastatin act synergistically to provide in vivo protection against lethal doses of SEB

Mulualem E. Tilahun, Alan Kwan, Kannan Natarajan, Megan Quinn, Ashenafi Y. Tilahun, Chen Xie, David H. Margulies, Barbara A. Osborne, Richard A. Goldsby, Govindarajan Rajagopalan

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Staphylococcal enterotoxin B (SEB) is one of a family of toxins secreted by Staphylococcus aureus that act as superantigens, activating a large fraction of the T-cell population and inducing production of high levels of inflammatory cytokines that can cause toxic shock syndrome (TSS) and death. Extracellular engagement of the TCR of T-cells and class II MHC of antigen presenting cells by SEB triggers the activation of many intracellular signaling processes. We engineered chimeric antibodies to block the extracellular engagement of cellular receptors by SEB and used a statin to inhibit intracellular signaling. Chimeric human-mouse antibodies directed against different neutralizing epitopes of SEB synergistically inhibited its activation of human T-cells in vitro. In the in vivo model of lethal toxic shock syndrome (TSS) in HLA-DR3 transgenic mice, two of these antibodies conferred significant partial protection when administered individually, but offered complete protection in a synergistic manner when given together. Similarly, in vivo, lovastatin alone conferred only partial protection from TSS similar to single anti-SEB antibodies. However, used in combination with one chimeric neutralizing anti-SEB antibody, lovastatin provided complete protection against lethal TSS in HLA-DR3 transgenic mice. These experiments demonstrate that in vivo protection against lethal doses of SEB can be achieved by a statin of proven clinical safety and chimeric human-mouse antibodies, agents now widely used and known to be of low immunogenicity in human hosts.

Original languageEnglish (US)
Article numbere27203
JournalPLoS One
Volume6
Issue number11
DOIs
StatePublished - Nov 15 2011

Fingerprint

lovastatin
Lovastatin
lethal dose
enterotoxins
septic shock
Poisons
antibodies
Septic Shock
Antibodies
T-cells
HLA-DR3 Antigen
Hydroxymethylglutaryl-CoA Reductase Inhibitors
T-lymphocytes
mice
T-Lymphocytes
lethal genes
neutralization
Transgenic Mice
Chemical activation
genetically modified organisms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Chimeric Anti-Staphylococcal enterotoxin B antibodies and lovastatin act synergistically to provide in vivo protection against lethal doses of SEB. / Tilahun, Mulualem E.; Kwan, Alan; Natarajan, Kannan; Quinn, Megan; Tilahun, Ashenafi Y.; Xie, Chen; Margulies, David H.; Osborne, Barbara A.; Goldsby, Richard A.; Rajagopalan, Govindarajan.

In: PLoS One, Vol. 6, No. 11, e27203, 15.11.2011.

Research output: Contribution to journalArticle

Tilahun, ME, Kwan, A, Natarajan, K, Quinn, M, Tilahun, AY, Xie, C, Margulies, DH, Osborne, BA, Goldsby, RA & Rajagopalan, G 2011, 'Chimeric Anti-Staphylococcal enterotoxin B antibodies and lovastatin act synergistically to provide in vivo protection against lethal doses of SEB', PLoS One, vol. 6, no. 11, e27203. https://doi.org/10.1371/journal.pone.0027203
Tilahun, Mulualem E. ; Kwan, Alan ; Natarajan, Kannan ; Quinn, Megan ; Tilahun, Ashenafi Y. ; Xie, Chen ; Margulies, David H. ; Osborne, Barbara A. ; Goldsby, Richard A. ; Rajagopalan, Govindarajan. / Chimeric Anti-Staphylococcal enterotoxin B antibodies and lovastatin act synergistically to provide in vivo protection against lethal doses of SEB. In: PLoS One. 2011 ; Vol. 6, No. 11.
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