Therapeutic inhibition of pro-inflammatory signaling and toxicity to staphylococcal enterotoxin B by a synthetic dimeric BB-loop mimetic of MyD88.

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)- α, interferon (IFN)-γ, interleukin (IL)-1β, 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-α and IL-1β 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.

• Authors: Teri L Kissner, Gordon Ruthel, Shahabuddin Alam, Enrique Mann, Dariush Ajami, Mitra Rebek, Eileen Larkin, Stefan Fernandez, Robert G Ulrich, Sun Ping, David S Waugh, Julius Rebek Jr, Kamal U Saikh
• Journal: PloS one (PLoS One) Vol. 7 Issue 7 Pg. e40773 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22848400 (Publication Type: Clinical Trial, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytokines
• Enterotoxins
• MYD88 protein, human
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• enterotoxin B, staphylococcal

Topics

• Animals
• Biomimetic Materials (chemistry, pharmacology)
• Cytokines (genetics, metabolism)
• Enterotoxins (toxicity)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Protein Structure, Secondary
• Protein Structure, Tertiary
• Signal Transduction (drug effects, genetics)