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.; Chen Xie; Margulies, David H.; Osborne, Barbara A.; Goldsby, Richard A.; Rajagopalan, Govindarajan
November 2011
PLoS ONE;2011, Vol. 6 Issue 11, p1
Academic Journal
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.


Related Articles

  • Engineering a soluble high-affinity receptor domain that neutralizes staphylococcal enterotoxin C in rabbit models of disease. Mattis, D.M.; Spaulding, A.R.; Chuang-Smith, O.N.; Sundberg, E.J.; Schlievert, P.M.; Kranz, D.M. // PEDS: Protein Engineering, Design & Selection;Feb2013, Vol. 26 Issue 2, p133 

    Superantigens (SAgs) are a class of immunostimulatory exotoxins that activate large numbers of T cells, leading to overproduction of cytokines and subsequent inflammatory reactions and systemic toxicity. Staphylococcal enterotoxin C (SEC), a SAg secreted by Staphylococcus aureus, has been...

  • Detection of superantigenic toxin genes in Staphylococcus aureus strains from subclinical bovine mastitis. Günaydın, Besime; Aslantaş, Özkan; Demir, Cemil // Tropical Animal Health & Production;Dec2011, Vol. 43 Issue 8, p1633 

    The aim of this study was to determine the presence of genes encoding enterotoxins ( sea- sej) and toxic shock syndrome toxin-1 ( tst) of Staphylococcus aureus strains ( n = 130) isolated from subclinical bovine mastitis in Turkey by polymerase chain reaction. Sixty-one (46.9%) isolates were...

  • An Enterotoxin-Like Protein in Staphylococcus aureus Strains from Patients with Toxic Shock Syndrome. Bergdoll, Merlin S.; Crass, Barbara A.; Reiser, Raoul F.; Robbins, Ruth N.; Lee, Amy C. M.; Chesney, P. Joan; Davis, Jeffrey P.; Vergeront, James M.; Wand, Philip J. // Annals of Internal Medicine;Jun82 Part 2, Vol. 96 Issue 6, p969 

    Deals with a study which examined the enterotoxigenicity of 142 Staphylococcus aureus strains isolated from patients with toxic shock syndrome. Materials and methods; Results; Discussion.

  • Uptake and Intracellular Trafficking of Superantigens in Dendritic Cells. Ganem, María B.; De Marzi, Mauricio C.; Fernández-Lynch, María J.; Jancic, Carolina; Vermeulen, Mónica; Geffner, Jorge; Mariuzza, Roy A.; Fernández, Marisa M.; Malchiodi, Emilio L. // PLoS ONE;Jun2013, Vol. 8 Issue 6, p1 

    Bacterial superantigens (SAgs) are exotoxins produced mainly by Staphylococcus aureus and Streptococcus pyogenes that can cause toxic shock syndrome (TSS). According to current paradigm, SAgs interact directly and simultaneously with T cell receptor (TCR) on the T cell and MHC class II (MHC-II)...

  • Neutralization of Multiple Staphylococcal Superantigens by a Single-Chain Protein Consisting of Affinity-Matured, Variable Domain Repeats. Xi Yang; Buonpane, Rebecca A.; Moza, Beenu; Nur-ur Rahman, A. K. M.; Ningyan Wang; Schlievert, Patrick M.; McCormick, John K.; Sundberg, Eric J.; Kranz, David M. // Journal of Infectious Diseases;8/1/2008, Vol. 198 Issue 3, p344 

    Staphylococcus aureus secretes various toxins that act as superantigens by stimulating a large fraction of the host's T cells. Toxin binding to variable domains of T cell receptor β chains (Vβ) leads to massive release of inflammatory molecules and potentially to toxic shock syndrome...

  • Neutralization of staphylococcal exotoxins in vitro by human-origin intravenous immunoglobulin. Chie Yanagisawa; Hideaki Hanaki; Taiji Natae; Keisuke Sunakawa // Journal of Infection & Chemotherapy (Springer Science & Business;Dec2007, Vol. 13 Issue 6, p368 

    Abstract  Human-origin intravenous immunoglobulin (IVIG) collected from healthy individuals was tested for its neutralizing activity against the hemolysin, toxic shock syndrome toxin-1 (TSST-1), and enterotoxins, produced by laboratory strains of methicillin-resistant Staphylococcus aureus...

  • Staphylococcus aureus Isolates from Irish Domestic Refrigerators Possess Novel Enterotoxin and Enterotoxin-like Genes and Are Clonal in Nature. Smyth, Davida S.; Kennedy, Jean; Twohig, Jane; Miajlović, Helen; Bolton, Declan; Smythi, Cyril J. // Journal of Food Protection;Apr2006, Vol. 69 Issue 3, p508 

    A previous study carried out by the National Food Centre in Dublin on bacterial contamination of Irish domestic refrigeration systems revealed that 41% were contaminated with Staphylococcus aureus. One hundred fifty-seven S. aureus isolates were screened by multiplex PCR analysis for the...

  • Toxic staph strain may be emerging.  // Hospital Infection Control & Prevention;Mar2009, Vol. 36 Issue 3, p32 

    The article reports on Staphylococcus aureus infection in the U.S. It states that the strain produced deletion mutant form of toxic shock syndrome toxin-1 (TST1) and variant enterotoxin C. The physiological effect of the TST1 is provided. It also presents the cases of two patients that describe...

  • Mesenchymal stromal (stem) cells suppress pro-inflammatory cytokine production but fail to improve survival in experimental staphylococcal toxic shock syndrome. Kim, Hani; Darwish, Ilyse; Monroy, Maria-Fernanda; Prockop, Darwin J.; Conrad Liles, W.; Kain, Kevin C. // BMC Immunology; 

    Background Toxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of proinflammatory cytokines...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics