FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

Abstract

Immunostimulating staphylococcal enterotoxin B (SEB) and related superantigenic toxins cause diseases in human beings and laboratory animals by hyperactivating cells of the immune system. These protein toxins bind to the major histocompatibility complex class II (MHC II) molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the stimulation of both monocytes/macrophages and T lymphocytes. The bridging of TCR with MHC II molecules by superantigens triggers intracellular signaling cascades, resulting in excessive release of proinflammatory mediators and massive polyclonal T-cell proliferation. The early induction of tumor necrosis factor α, interleukin 1 (IL-1), interleukin 2 (IL-2), interferon gamma (IFNγ), and macrophage chemoattractant protein 1 promotes fever, inflammation, and multiple organ injury. The signal transduction pathways for staphylococcal superantigen-induced toxicity downstream from TCR/major histocompatibility complex (MHC) ligation and interaction of cell surface co-stimulatory molecules include the mitogen-activated protein kinase cascades and cytokine receptor signaling, activating nuclear factor κB (NFκB) and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. Knowledge of host regulation within these activated pathways and molecules initiated by SEB and other superantigens enables the selection of US Food and Drug Administration (FDA)-approved drugs to interrupt and prevent superantigen-induced shock in animal models. This review focuses on the use of FDA-approved immunosuppressants in targeting the signaling pathways induced by staphylococcal superantigens.

Cellular immune response of Staphylococcus aureus enterotoxin B in Balb/c mice through intranasal infection

“…Monocytes also doubled by day 6 and continued to increase through day 22. Bacterial superantigens can upregulate TLR expression in primary human monocytes by ligation of MHC Class II [25].…”

Influence of Phosphatidylinositol-3-Kinase/Protein Kinase B-Mammalian Target of Rapamycin Signaling Pathway on the Neuropathic Pain Complicated by Nucleoside Reverse Transcriptase Inhibitors for the Treatment of HIV Infection

“…[ 18 19 ] Rapamycin, which has mainly been used in the study of the pathogenesis and treatment of tumors and immune diseases, specifically inhibits the activity of mTOR. [ 20 21 ] Recent study has shown that rapamycin is a promising tool for the mechanistic study and treatment of pain. [ 22 ] In the present study, changes in behavior and protein expression related to the Akt/mTOR signaling pathway after the induction of neuropathic pain by oral administration of stavudine were investigated in mice.…”