Late Multiple Organ Surge in Interferon-Regulated Target Genes Characterizes Staphylococcal Enterotoxin B Lethality

Ferreyra, Gabriela A.; Elinoff, Jason M.; Demirkale, Cumhur Y; Starost, Matthew F.; Buckley, Marilyn; Munson, Peter J.; Krakauer, Teresa; Danner, Robert L.

doi:10.1371/journal.pone.0088756

Cited by 22 publications

(44 citation statements)

References 82 publications

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“…27-29 Augmented expression of Irf8, Iigp1, Gbp2, Gbp3, and Gbp6 mRNA has also been described as part of a disseminated interferon-response gene expression signature of 84 genes that can be detected in immune cells and peripheral organs such as kidney and lung of mice after challenge with S. aureus enterotoxin, 30 possibly reflecting immune cell infiltration of these tissues. We therefore analyzed RNA samples prepared 16 hours after endotoxemia induction by LPS from unfractionated lung and kidney tissue, and from fluorescence-activated cell sorter (FACS)-purified CD11bGr1 POS cells.…”

Section: Epcr and Par2 Deficiency Attenuate Lps-induced In Vivo Exprementioning

confidence: 99%

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

Liang

Kerschen

Hernández

et al. 2015

Blood

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Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrowderived myeloid cells and in monocytic RAW264.7 cells, the LPS-induced expression of functionally active TF, assembly of the ternary TF-VIIa-Xa initiation complex of blood coagulation, and the EPCR-dependent activation of protease-activated receptor 2 (PAR2) by the ternary TF-VIIa-Xa complex were required for the normal LPS induction of messenger RNAs encoding the TLR3/4 signaling adaptor protein Pellino-1 and the transcription factor interferon regulatory factor 8. In response to in vivo challenge with LPS, mice lacking EPCR or PAR2 failed to fully initiate an interferon-regulated gene expression program that included the Irf8 target genes Lif, Iigp1, Gbp2, Gbp3, and Gbp6. The inflammation-induced expression of TF and crosstalk with EPCR, PAR2, and TLR4 therefore appear necessary for the normal evolution of interferon-regulated host responses. (Blood. 2015;125(18):2845-2854

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Section: Epcr and Par2 Deficiency Attenuate Lps-induced In Vivo Exprementioning

confidence: 99%

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

Liang

Kerschen

Hernández

et al. 2015

Blood

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“…Furthermore , FAM26F is rapidly induced after stimulation as shown in the in vitro assays, in vivo studies in human PBMCs after vaccination (Matsumiya et al , 2014) and in mice 5 h after staphylococcal enterotoxin B exposure (Ferreyra et al , 2014) and represents therefore an early/immediate IFN-induced gene. Current knowledge on regulation of FAM26F transcription and action as well as its potential effects on T-cells is shown in Fig.…”

Section: Discussionmentioning

confidence: 98%

Pre-infection transcript levels of FAM26F in peripheral blood mononuclear cells inform about overall plasma viral load in acute and post-acute phase after simian immunodeficiency virus infection

Javed

Leuchte

Salinas

et al. 2016

Journal of General Virology

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CD8+ cells from simian immunodeficiency virus (SIV)-infected long-term non-progressors and some uninfected macaques can suppress viral replication in vitro without killing the infected cells. The aim of this study was to identify factors responsible for non-cytolytic viral suppression by transcriptional profiling and to investigate their potential impact on SIV replication. Results of microarray experiments and further validation with cells from infected and uninfected macaques revealed that FAM26F RNA levels distinguished CD8+ cells of controllers and non-controllers (P=0.001). However, FAM26F was also expressed in CD4+ T-cells and B-cells. FAM26F expression increased in lymphocytes after in vitro IFN-γ treatment on average 40-fold, and ex vivo FAM26F RNA levels in peripheral blood mononuclear cells correlated with plasma IFN-γ but not with IFN-α. Baseline FAM26F expression appeared to be stable for months, albeit the individual expression levels varied up to tenfold. Investigating its role in SIV-infection revealed that FAM26F was upregulated after infection (P<0.0008), but did not directly correlate with viral load in contrast to MX1 and CXCL10. However, pre-infection levels of FAM26F correlated inversely with overall plasma viral load (AUC) during the acute and post-acute phases of infection (e.g. AUC weeks post infection 0–8; no AIDS vaccine: P<0.0001, Spearman rank correlation coefficient (rs)=−0.89, n=16; immunized with an AIDS vaccine: P=0.033, rs=−0.43; n=25). FAM26F transcript levels prior to infection can provide information about the pace and strength of the antiviral immune response during the early stage of infection. FAM26F expression represented, in our experiments, one of the earliest prognostic markers, and could supplement major histocompatibility complex (MHC)-typing to predict disease progression before SIV-infection.

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“…Increased protein synthesis, ROS, and activated PKC from cell activation are upstream activators of endoplasmic reticulum (ER) stress 83. SEB induces the expression of ubiquitin ligases, proteasome peptidases, and immunoproteasomes in multiple organs 84. These ER stress response genes are likely a result of Ca ++ flux, misfolded proteins, and activated PKC.…”

Section: Cellular Response To Superantigensmentioning

confidence: 99%

“…IFNγ triggers innate host defense responses, antiviral genes, apoptotic programs, and immunoproteasomes and has many immunomodulatory functions. The cell death pathway triggered in vitro and in vivo by superantigens includes genes associated with apoptosis, such as FADD, death receptor ligand TRAIL (TNFSF10), caspases, CARD, and phospholipid scramblase 1 (PLSCR1) 84,96,97. These genes are observed in superantigen-activated PBMC and major organs from the “double-hit” SEB model.…”

Section: Cellular Response To Superantigensmentioning

confidence: 99%

“…These genes are observed in superantigen-activated PBMC and major organs from the “double-hit” SEB model. Cellular injury is also apparent from the expression of MMPs, cathepsins, and other cell matrix breakdown products such as versican and fibronectin in superantigen-activated cells 84,97. DNA damage repair enzymes, poly(ADP-ribose) polymerases, are induced in PBMC and multiple organs of the “double-hit SEB” mouse model, indicating DNA damage and repair 84…”

Section: Cellular Response To Superantigensmentioning

confidence: 99%

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FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

Krakauer¹

2017

ITT

Self Cite

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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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Late Multiple Organ Surge in Interferon-Regulated Target Genes Characterizes Staphylococcal Enterotoxin B Lethality

Cited by 22 publications

References 82 publications

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

Pre-infection transcript levels of FAM26F in peripheral blood mononuclear cells inform about overall plasma viral load in acute and post-acute phase after simian immunodeficiency virus infection

FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

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