Chemotherapeutics Targeting Immune Activation by Staphylococcal Superantigens
ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
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Staphylococcal enterotoxin B SEB and related superantigenic toxins are potent activators of the immune system and cause a variety of diseases in humans, ranging from food poisoning to toxic shock. These toxins bind to both MHC class II molecules and specific V-beta regions of T cell receptors TCR, resulting in the activation of both monocytesmacrophages and T lymphocytes. The interactions of these toxins with host cells lead to excessive production of proinflammatory cytokines and T cell proliferation, causing clinical symptoms that include fever, hypotension and shock. Different domains of SEB contributing to MHC class II or TCR interactions have been mapped and defined by mutagenesis, crystallography and other biochemical techniques. This review summarizes the in vitro and in vivo effects of staphylococcal superantigens, and the therapeutic agents to mitigate their toxic effects. Potential targets to prevent the toxic effects of bacterial superantigens include blocking the interaction of SEs with MHC or TCR, or other costimulatory molecules inhibition of signal transduction pathways used by these superantigens inhibition of cytokine and chemokine production and inhibition of the downstream signaling pathways used by proinflammatory cytokines and chemokines. Early blockade of these targets proves to be useful in vitro and in vivo testing of therapeutics against SEB-induced toxic shock will also be reviewed.