Accession Number : ADA546538


Title :   A Small Molecule that Mimics the BB-Loop in the Toll/IL-1 Receptor Domain of MyD88 Attenuates Staphylococcal Enterotoxin B Induced Pro-Inflammatory Cytokine Production and Toxicity in Mice


Descriptive Note : Journal article


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


Personal Author(s) : Kissner, Teri L ; Moisan, Lionel ; Mann, Enrique ; Alam, Shahabuddin ; Ruthel, Gordon ; Ulrich, Robert G ; Rebek, Mitra ; Rebek, Jr, Julius ; Saikh, Kamal U


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a546538.pdf


Report Date : Jun 2011


Pagination or Media Count : 22


Abstract : Toxic shock syndrome (TSS) is a clinical consequence of the profound amplification of host pro-inflammatory cytokine signaling that results from staphylococcal enterotoxin (SE) exposure. We recently reported that MyD88-/- mice were resistant to SEA or SEB toxic shock and displayed reduced levels of pro-inflammatory cytokines in their serum. Here we report that SEB stimulation of total mononuclear cells up-regulated MyD88 in monocytes and T cells. Further, MyD88 gene silencing in primary human cells using siRNA prevented SEB or SEB plus lipopolyaccharide (LPS) induction of interleukin-1 Beta (IL-1 Beta) transcriptional activation, suggesting that MyD88-mediated signaling is an essential component of SEB toxicity. We synthesized small molecules that mimic the conserved BBloop in the Toll/IL-1 receptor (TIR) domain of MyD88. In primary human cells, these mimetics attenuated SEB-induced proinflammatory cytokine production. SEB stimulation of primary cells with mimetic affected newly synthesized MyD88 and downstream signaling components. Furthermore, LPS-induced MyD88 signaling was likewise inhibited in a cell-based reporter assay. More importantly, administration of mimetic reduced cytokine responses and increased survivability in a murine SEB challenge model. Collectively, these results suggest that MyD88 BB-loop mimetics interfere with SEB-induced proinflammatory signaling and toxicity, thus offering a potential approach in the therapy of toxic shock.


Descriptors :   *ENTEROTOXINS , MOLECULES , CYTOKINES , STAPHYLOCOCCUS , SHOCK(PATHOLOGY) , STIMULATION(PHYSIOLOGY) , CELLS(BIOLOGY)


Subject Categories : Anatomy and Physiology
      Toxicology


Distribution Statement : APPROVED FOR PUBLIC RELEASE