Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

Krakauer, Teresa; Buckley, Marilyn

doi:10.3390/toxins4090718

Cited by 14 publications

(13 citation statements)

References 35 publications

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“…More recent studies indicate that mTORC1 regulates T-cell differentiation and Treg function 138,139. Rapamycin inhibits cytokine release and T-cell proliferation by blocking mTORC1 signaling induced by SEB 125,140. Rapamycin protects mice from SEB-induced shock even when administered 1 day after SEB administration, providing an effective drug postexposure 140.…”

Section: Repurposing Of Us Food and Drug Administration (Fda)-approvementioning

confidence: 99%

FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

Krakauer¹

2017

ITT

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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.

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Section: Repurposing Of Us Food and Drug Administration (Fda)-approvementioning

confidence: 99%

FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

Krakauer¹

2017

ITT

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“…Rapamycin blocked SEB-induced T-cell proliferation, reduced serum cytokines, and prevented hypothermia and weight loss induced by SEB. Intranasal rapamycin also protected mice against SEB-induced shock when administered as late as 17 h after toxin exposure, providing a practical route of drug delivery against SEB [142]. Another structural analog of rapamycin, tacrolimus, suppressed superantigen-induced T-cell activation in vitro but did not reduce lethality in HLA-DR3 transgenic mice [143].…”

Section: Inhibitors Of Signal Transduction and Cytokinesmentioning

confidence: 99%

“…However, as seen from the various FDA-approved drugs tested, even knowing the mechanism of action of these drugs is no guarantee for success as in vivo dosages, dosing routes and schedules as well as animal models all affect the outcome. Rapamycin, by decreasing the levels and effects of IL-2 and IFNγ through mTOR inhibition, is proven to be the most effective single agent to counter both intranasal and systemic exposure to SEB [77,142]. …”

Section: Repurposing Of Fda-approved Drugs For Biodefense Agentsmentioning

confidence: 99%

Update on Staphylococcal Superantigen-Induced Signaling Pathways and Therapeutic Interventions

Krakauer

2013

Toxins

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Staphylococcal enterotoxin B (SEB) and related bacterial toxins cause diseases in humans and laboratory animals ranging from food poisoning, acute lung injury to toxic shock. These superantigens bind directly to the major histocompatibility complex class II molecules on antigen-presenting cells and specific Vβ regions of T-cell receptors (TCR), resulting in rapid hyper-activation of the host immune system. In addition to TCR and co-stimulatory signals, proinflammatory mediators activate signaling pathways culminating in cell-stress response, activation of NFκB and mammalian target of rapamycin (mTOR). This article presents a concise review of superantigen-activated signaling pathways and focuses on the therapeutic challenges against bacterial superantigens.

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“…Rapamycin works by suppressing mTOR activities resulting in inhibition of SEB-induced T cell proliferation, reduced IL-2 and IFNγ. Another study indicates rapamycin was effective as an intranasal drug, providing practical protection against SEB-induced shock even 17 h after toxin exposure [137]. …”

Section: Inhibitors Of Signal Transductionmentioning

confidence: 99%

PI3K/Akt/mTOR, a Pathway Less Recognized for Staphylococcal Superantigen-Induced Toxicity

Krakauer

2012

Toxins

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Immunostimulating staphylococcal enterotoxin B (SEB) and related superantigenic toxins cause diseases in humans and laboratory animals by activating cells of the immune system. These toxins bind directly to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and specific Vβ regions of T-cell receptors (TCR), resulting in hyperactivation of both T lymphocytes and monocytes/macrophages. Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines, especially tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 causing clinical symptoms of fever, hypotension, and shock. The well-explored signal transduction pathways for SEB-induced toxicity downstream from TCR/MHC ligation and interaction of cell surface co-stimulatory molecules include the mitogen-activated protein kinase cascades and cytokine receptor signaling, culminating in NFκB activation. Independently, IL-2, IFNγ, and chemokines from activated T cells signal via the phosphoinositide 3-kinase (PI3K), the serine/threonine kinases, Akt and mammalian target of rapamycin (mTOR) pathways. This article reviews the signaling molecules induced by superantigens in the activation of PI3K/Akt/mTOR pathways leading to staphylococcal superantigen-induced toxicity and updates potential therapeutics against superantigens.

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Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

Cited by 14 publications

References 35 publications

FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

Update on Staphylococcal Superantigen-Induced Signaling Pathways and Therapeutic Interventions

PI3K/Akt/mTOR, a Pathway Less Recognized for Staphylococcal Superantigen-Induced Toxicity

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