Accession Number : ADA565608


Title :   Therapeutic Inhibition of Pro-Inflammatory Signaling and Toxicity to Staphylococcal Enterotoxin B by a Synthetic Dimeric BB-Loop Mimetic of MyD88


Descriptive Note : Journal article


Corporate Author : ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD


Personal Author(s) : Kissner, Teri L ; Ruthel, Gordon ; Alam, Shahabuddin ; Mann, Enrique ; Ajami, Dariush ; Rebek, Mitra ; Larkin, Eileen ; Fernandez, Stefen ; Ulrich, Robert G ; Ping, Sun


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a565608.pdf


Report Date : 27 Jul 2012


Pagination or Media Count : 14


Abstract : Staphylococcal enterotoxin B (SEB) exposure triggers an exaggerated pro-inflammatory cytokine response that often leads to toxic shock syndrome (TSS) associated with organ failure and death. MyD88 mediates pro-inflammatory cytokine signaling induced by SEB exposure and MyD88-/- mice are resistant to SEB intoxication, suggesting that MyD88 may be a potential target for therapeutic intervention. We targeted the BB loop region of the Toll/IL-1 receptor (TIR) domain of MyD88 to develop small-molecule therapeutics. Here, we report that a synthetic compound (EM-163), mimic to dimeric form of BB-loop of MyD88 attenuated tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1Beta, IL-2 and IL-6 production in human primary cells, whether administered pre- or post-SEB exposure. Results from a direct binding assay and from MyD88 co-transfection/co-immunoprecipitation experiments, suggest that EM-163 inhibits TIR-TIR domain interaction. Additional results indicate that EM-163 prevents MyD88 from mediating downstream signaling. In an NF-kB-driven reporter assay of lipopolysaccharide-stimulated MyD88 signaling, EM-163 demonstrated a dose-dependent inhibition of reporter activity as well as TNF-alpha and IL-1Beta production. Importantly, administration of EM-163 pre- or post exposure to a lethal dose of SEB abrogated pro-inflammatory cytokine responses and protected mice from toxic shock-induced death. Taken together, our results suggest that EM-163 exhibits a potential for therapeutic use against SEB intoxication.


Descriptors :   *ENTEROTOXINS , *INHIBITION , *PROTEINS , CYTOKINES , INFLAMMATION , REPRINTS , STAPHYLOCOCCUS , TOXICITY


Subject Categories : Biochemistry
      Toxicology
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE